Orexin receptor antagonists

ABSTRACT

The disclosures herein relate to novel compounds of formula wherein W, X and Y 1 , Y 2 , Y 3  and Y 4  are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of neurological or psychiatric disorders associated with orexin receptors.

RELATED APPLICATION INFORMATION

This application is a continuation of U.S. application Ser. No.14/411,269, filed Dec. 24, 2014, which is a 371 of InternationalApplication No. PCT/GB2013/051761, filed Jul. 3, 2013, which claimsbenefit of U.S. Provisional Application No. 61/667,540, filed Jul. 3,2012, all of which are incorporated herein by reference.

This application relates to novel compounds and their use as orexinreceptor antagonists. Compounds described herein may be useful in thetreatment or prevention of diseases in which orexin receptors areinvolved. The application is also directed to pharmaceuticalcompositions comprising these compounds and the manufacture and use ofthese compounds and compositions in the prevention or treatment of suchdiseases in which orexin receptors are involved.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide). Two orexin receptors havebeen studied in mammals, both belonging to the super family of G-proteincoupled receptors. The orexin-1 receptor (OX₁ or OX1R) is selective forOX-A and the orexin-2 receptor (OX₂ or OX2R) is capable to bind OX-A aswell as OX-B. The physiological actions in which orexins are presumed toparticipate are thought to be expressed via one or both of OX₁ receptorand OX₂ receptor as the two subtypes of orexin receptors.

Orexins also regulate states of sleep and wakefulness, openingpotentially novel medicament based therapeutic approaches fornarcoleptic or insomniac patients. Orexin receptors are found in themammalian brain and may have numerous implications in pathologiesrelated to general orexin system dysfunction. Prior art compounds forthe treatment of orexin system dysfunction are shown in, for exampleWO2008008517 and WO2010122151. The structures of the compounds containedin these prior art disclosures are entirely different to the structuresdisclosed below.

The most advanced orexin receptor antagonists are almorexant, suvorexant(MK-4305) and MK-6096; these compounds are dual orexin receptorantagonists (DORA), displaying similar affinities for both OX₁ and OX₂receptor subtypes. These compounds have been shown to be effective inpromoting sleep in preclinical species, reducing active wake andincreasing both non-REM and REM sleep in rodent and dog studies. In aPhase II clinical trial, almorexant dose-dependently increased sleepefficiency in patients with primary insomnia and tended to improve wakeafter sleep onset and reduce the latency to persistent sleep. Similarly,suvorexant increased sleep efficiency in a Phase IIb study; significantdose-related effects were also observed for sleep induction andmaintenance parameters, and has shown efficacy in several Phase IIItrials in primary insomnia patients. In both cases, DORAs were welltolerated. MK-6096 shows efficacy in preclinical sleep models and hascompleted a Phase II clinical trial evaluating efficacy in the treatmentof patients with primary insomnia.

Orexins have been found to stimulate food consumption in rats,suggesting a physiological role for these peptides as mediators in thecentral feedback mechanism that regulates feeding behaviour. Orexin-A isbelieved to be an endogenous regulator of appetite and an OX₁ receptorantagonist reduces food intake in rats. Antagonists of the orexin-Areceptor(s) may therefore be useful in the treatment of obesity anddiabetes via regulation of appetite. Orexin receptor antagonists mayalso be useful in the treatment of binge eating disorder and othercompulsive disorders including impulse control disorders. The search fornew therapies to treat obesity and other eating disorders is animportant and increasing challenge, particularly in westernisedsocieties. Current treatments for obesity and diabetes are often eitherineffective or show unacceptably high toxicity.

Orexinergic neurons project from the lateral hypothalamus to the ventraltegmental area, amygdala, nucleus accumbens and pre-frontal cortex,indicating a role in reward pathways. Orexin receptor antagonists havebeen shown to ameliorate sensitisation, withdrawal andself-administration of a number of drugs of abuse in animal models,suggesting that such compounds could have utility in the treatment ofdependence and addiction. Many of the regions innervated and modulatedby orexin neurons are dopaminergic, suggesting an interplay betweenthese neurotransmitter systems. Antagonists of orexin receptors couldmodulate central dopaminergic transmission and be effective in thetreatment of movement disorders in which dopamine levels are abnormal.

Orexin peptides also play a role in arousal, vigilance and incentrally-controlled autonomic function and have been shown to beinvolved in the development of a panic-prone state in rodents, an effectthat could be reversed by orexin receptor antagonists, suggesting thatthese would have utility in the treatment of anxiety and panic.Furthermore, levels of beta-amyloid, the pathological hallmark ofAlzheimer's disease, were increased by sleep deprivation and orexinpeptide infusion in mice. In contrast, levels of beta-amyloid andamyloid placque formation were reduced in amyloid precursor proteintransgenic mice upon treatment with an orexin receptor antagonist,suggesting that such compounds may have utility in the treatment ofAzheimer's disease and other dementia-related cognitive dysfunction.

MK-6096 has also completed a Phase II trial evaluating safety andefficacy versus placebo for preventing migraines in participants withepisodic migraine. This observation suggests that orexin receptorantagonists may have utility in the treatment or prevention of migraineor other headache disorders, such as tension-type headache, clusterheadache, other trigeminal autonomic cephalalgias, other primaryheadaches such as hemicrania continua or those listed in theInternational Headache Society 2nd Edition of The International HeadacheClassification (ICHD-2), secondary headaches such as those listed inICHD-2, cranial neuralgias such as trigeminal neuralgia or those listedin ICHD-2, or other causes of headache, cranial neuralgia, central orprimary facial pain such as those listed in ICHD-2.

A Phase II trial of MK-6096 is currently recruiting to evaluate thesafety and efficacy as an adjunctive therapy in participants with majordepressive disorder and partial response to antidepressant monotherapy.This observation suggests that orexin receptor antagonists may haveutility in the treatment of depression and related disorders.

MK-6096 has also completed a Phase II trial evaluating safety andefficacy in the treatment of painful diabetic neuropathy (PDN) inadults. This observation suggests that orexin receptor antagonists mayhave utility in the treatment of neuropathic pain or other paindisorders.

Whilst there has been disclosure of related compounds in the priorchemical art, there has been no disclosure of chemically relatedcompounds as antagonists of orexin receptors or for the treatment oforexin system dysfunction.

SUMMARY OF THE INVENTION

The invention relates to novel compounds. The invention further relatesto the first medical use of known compounds. The invention also relatesto the use of both novel and known compounds as antagonists of orexinreceptors or for the treatment of orexin system dysfunction. Theinvention further relates to the use of both novel and known compoundsin the manufacture of medicaments for use as orexin receptor antagonistsor for the treatment of orexin system dysfunction. The invention furtherrelates to compounds, compositions and medicaments for the treatment ofdiabetes, obesity, insomnia, neurological or psychiatric disorders.Embodiments of the invention may be compounds according to the formula

wherein Y₁, Y₂, Y₃ and Y₄ are independently an optionally substitutedcarbon or a nitrogen atom and W is an methylene group substituted by asubstituted aryl, or optionally substituted heteroaryl orheterocycloalkyl moiety; and X comprises an optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted heterocycloalkyl moiety; and wherein either atleast one of Y₁-Y₄ is a nitrogen atom; or X comprises an optionallysubstituted heteroaryl, or optionally substituted heterocycloalkylmoiety; or W is a moiety of formula

wherein R′ and R″ are independently H or alkyl and R′″ is2,4,6-trisubstituted aryl, or optionally substituted heteroaryl group.

Alternative embodiments of the invention may be a compound of formula

wherein Y₁, Y₂, Y₃ are independently an optionally substituted carbon ora nitrogen atom; and Y₄ is is C-alkyl, C-halogen, C—H or N and W is amethylene group substituted by an optionally substituted aryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl or optionally substituted heteroaryl moiety; and Xcomprises an optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, or optionally substitutedheterocycloalkyl moiety, wherein X is not cyclopropyl, for use inmedicine.

FIGURES

FIG. 1: A schematic of different routes available to prepare compoundsdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel compounds. In the cases where compoundsare novel, the compounds themselves may be claimed. In cases where thecompounds have been synthesised previously, but no medical use has beenreported, the first medical use of known compounds may be claimed. Theinvention also relates to the use of both novel and known compounds asantagonists of orexin receptors or for the treatment of orexin systemdysfunction. The invention further relates to the use of compounds inthe manufacture of medicaments for use as orexin receptor antagonists orfor the treatment of orexin system dysfunction. The invention furtherrelates to compounds, compositions and medicaments for the treatment ofinsomnia, migraine, cluster headache and other headache disorders,diabetes, obesity, substance dependence, addiction, movement disorders,anxiety disorders, panic disorders, cognitive impairment or Alzheimer'sdisease.

Thus, in specific embodiments the present invention provides methods fortreating, preventing, ameliorating, controlling or reducing the risk ofa variety of neurological and psychiatric disorders associated withorexin receptors, including disturbed biological and circadian rhythms,sleep disorders, sleep disturbances, including enhancing sleep quality,improving sleep quality, increasing sleep efficiency, augmenting sleepmaintenance; increasing the value which is calculated from the time thata subject sleeps divided by the time that a subject is attempting tosleep; improving sleep initiation; decreasing sleep latency or onset(the time it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; altering the timing, frequency or duration of REM sleepbouts; altering the timing, frequency or duration of slow wave sleepbouts; reducing daytime drowsiness; treating or reducing excessivedaytime sleepiness, REM sleep interruptions, sleep apnea, narcolepsy,insomnia, parasomnia, jet-lag, shift workers' sleep disturbances,dyssomnias, night terror, sleep disturbances associated with diseasessuch as neurological disorders, insomnias associated with depression,emotional/mood disorders, Alzheimer's disease or cognitive impairment,as well as sleep walking and enuresis, and sleep disorders whichaccompany aging.

In addition, the present invention provides methods for treatment ofpain disorders including neuropathic pain and restless leg syndrome,migraine, cluster headache, tension-type headache, trigeminal autonomiccephalalgias, hemicrania continua, trigeminal neuralgia, other headachedisorders, hyperalgesia, pain, enhanced or exaggerated sensitivity topain such as hyperalgesia, causalgia, and allodynia, acute pain, burnpain, atypical facial pain, neuropathic pain, back pain, complexregional pain syndrome I and II, arthritic pain, sports injury pain,pain related to infection e.g. HIV, post-chemotherapy pain, post-strokepain, post-operative pain, neuralgia, conditions associated withvisceral pain such as irritable bowel syndrome, and angina;obesity-related disorders including overeating and bulimia nervosa,hypertension, congestive heart failure, pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, diabetes, impaired glucosetolerance; cardiovascular disease including acute and congestive heartfailure, hypotension, hypertension, angina pectoris, myocardinalinfarction; eating disorders including anorexia, cachexia, addictivefeeding behaviors; binge/purge feeding behaviours such as binge eatingdisorder, appetite/taste disorders; addictive behaviours includingdependence or withdrawal from substances including, but not limited to,alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics;tolerance to narcotics or withdrawal from narcotics; movement disordersincluding Parkinson's disease, akinesias, drug-induced parkinsonism,dystonia, restless leg syndrome; anxiety or panic disorders includinggeneralized anxiety disorder, panic disorder, obsessive compulsivedisorder and impulse control disorder; cancer including bowel, colon,stomach, breast, endometrial, pancreatic or prostate cancer;hypothalamic/pituitary diseases including Cushing's syndrome/disease,basophile adenoma, prolactinoma, hyperprolactinemia, hypophysistumour/adenoma, hypothalamic diseases, Froehlich's syndrome,adrenohypophysis disease, hypophysis disease, adrenohypophysishypofunction, adrenohypophysis hyperfunction, hypothalamic hypogonadism,Kallman's syndrome (anosmia, hyposmia), functional or psychogenicamenorrhea, hypopituitarism, hypothalamic hypothyroidism,hypothalamic-adrenal dysfunction, idiopathic hyperprolactinemia,hypothalamic disorders of growth hormone deficiency, idiopathic growthdeficiency, dwarfism, gigantism, acromegaly; psychiatric disordersincluding depression, anxiety, addictions, affective neurosis,depressive neurosis, anxiety neurosis, dysthymic disorder, behaviourdisorder, mood disorder, sexual dysfunction, psychosexual dysfunction,sex disorder, schizophrenia, manic depression, delirium, severe mentalretardation; other CNS disorders including dementia, dyskinesias such asHuntington's disease and Tourette syndrome, ischemic or haemorrhagicstroke, subarachnoid haemorrhage, nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex,pallido-ponto-nigral degeneration, epilepsy, seizure disorders;inflammatory disorders including inflammatory bowel disease;renal/urinary disorders including urinary retention, benign prostatichypertrophy, chronic renal failure, renal disease; cognitive impairmentor Alzheimer's disease in a mammalian patient in need thereof whichcomprises administering to the patient a therapeutically effectiveamount of a compound of the present invention.

Compounds exemplified herein are based around the structure:

In which any of Y₁, Y₂, Y₃ or Y₄ are independently carbon atoms ornitrogen atoms. The carbon atoms Y₁, Y₂, Y₃ or Y₄ may bear hydrogenatoms (i.e. form CH groups) or may be substituted, for example with halogroups (fluoro, chloro, bromo or iodo), hydroxyl groups, alkyl groups orsubstituted alkyl groups, alkenyl or alkynyl groups or alkoxy groups.For example any of Y₁, Y₂, Y₃ or Y₄ may be independently N, C—H, C—F,C—Cl, C—Br, C—I, C-alkyl or C—OH. The alkyl groups may be for examplemethyl, ethyl, propyl or any other alkyl group as defined under thedefinitions of alkyl groups found herein. The alkyl, alkenyl or alkynylgroup may contain 1-4 carbon atoms. The alkyl group may be a cyclicgroup such as cyclopropyl or cyclobutyl. Preferably, no more than one ofY₁, Y₂, Y₃ and Y₄ is N. In particular examples Y₁ may be nitrogen.Alternatively, in particular examples, Y₃ may be nitrogen. In particularexamples Y₁ or Y₃ may be CF. Each of Y₁-Y₄ may be C—H. Y₄ may be CH orN.

In certain prior art compounds, for example as disclosed in PCTapplication WO2007108569, Y₄ has been described for a variety of carbonlinked mono, bi or tri cyclic amino groups. All medical uses of thecompounds described in WO2007108569 require that Y₄ is a carbon atomlinked to a nitrogen atom. The preparation of said compounds was carriedout using intermediates where Y₄ consists of a carbon-halogen bond, orsimilar reactive leaving group. This prior art does not disclosecompounds as disclosed herein wherein X and W are both ring structuresas described herein where Y₄ is CH, or where Y₄ is a nitrogen atom inthe ring itself. Furthermore, said document does not disclose a medicaluse for the synthetic intermediates where Y₄ is CF, CCl, CBr or Cl, andthus the medical use of any compound as described herein is notdisclosed with the exception of where Y₄ contains a nitrogen atom linkedto the aromatic carbon of Y₄.

In particular aspects, compounds of the invention may be exemplifiedherein based around the structure:

in which any of Y₂, Y₃ or Y₄ are independently carbon atoms or nitrogenatoms. The carbon atoms Y₂, Y₃ or Y₄ may be further substituted, forexample with halo groups (fluoro, chloro, bromo or iodo), hydroxylgroups, alkyl groups or substituted alkyl groups, alkenyl or alkynylgroups or alkoxy groups. For example any of Y₂, Y₃ or Y₄ may beindependently N, C—H, C—F, C—Cl, C—Br, C—I, C-alkyl or C—OH. The alkylgroups may be for example methyl, ethyl, propyl or any other alkyl groupas defined under the definitions of alkyl groups found herein. Thealkyl, alkenyl or alkynyl group may contain 1-4 carbon atoms. The alkylgroup may be a cyclic group such as cyclopropyl or cyclobutyl. W is amethylene group or CH(alkyl) group substituted by an optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl or optionally substituted heteroarylmoiety. X comprises an optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, or optionallysubstituted heterocycloalkyl moiety.

In particular aspects, compounds of the invention may be exemplifiedherein based around the structure:

in which any of Y₁, Y₂ or Y₄ are independently carbon atoms or nitrogenatoms. The carbon atoms Y₁, Y₂ or Y₄ may be further substituted, forexample with halo groups (fluoro, chloro, bromo or iodo), hydroxylgroups, alkyl groups or substituted alkyl groups, alkenyl or alkynylgroups or alkoxy groups. For example any of Y₁, Y₂ or Y₄ may beindependently N, C—H, C—F, C—Cl, C—Br, C—I, C-alkyl or C—OH. The alkylgroups may be for example methyl, ethyl, propyl or any other alkyl groupas defined under the definitions of alkyl groups found herein. Thealkyl, alkenyl or alkynyl group may contain 1-4 carbon atoms. The alkylgroup may be cyclic groups such as cyclopropyl or cyclobutyl. W is amethylene group or CH(alkyl) group substituted by an optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl or optionally substituted heteroarylmoiety. X comprises an optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, or optionallysubstituted heterocycloalkyl moiety.

The moiety W may be a methylene group substituted by a substituted aryl,or optionally substituted heteroaryl or heterocycloalkyl moiety.

The substituted aryl and heteroaryl groups may be any of the aryl andheteroaryl groups listed below in the “Definitions” section of thisapplication.

Typically, however, the aryl group is a phenyl group which issubstituted as defined herein.

The heteroaryl group, which may be optionally substituted as definedherein, can be monocyclic or polycyclic (e.g bicyclic or tricyclic) andmay, for example, contain up to 14 ring members, more typically 5 to 10.When the heteroaryl group is monocyclic, preferably it is 5- or6-membered. The heteroaryl (e.g. 5- or 6-membered heteroaryl) groupcontains one or more (e.g. 1, 2 or 3) heteroatoms which are typicallyselected from nitrogen, oxygen and sulphur. Examples of heteroarylgroups are 5- and 6-membered heteroaryl groups containing a nitrogenatom ring member and optionally a second heteroatom ring member selectedfrom nitrogen, oxygen and sulphur. Particular heteroaryl groups arepyridyl and pyrazolyl groups

In one embodiment, W is a methylene group substituted with a substitutedphenyl, or optionally substituted monocyclic 5- or 6-membered heteroarylmoiety containing up to two heteroatom ring members selected fromnitrogen, oxygen and sulphur.

In a further embodiment, W is a methylene group substituted with asubstituted phenyl or optionally substituted pyridyl or pyrazolyl group.

As defined herein, the aryl group forming part of W is substituted andthe heteroaryl group is optionally substituted. The substituents may beas defined below in the “Definitions” section below.

In one general embodiment, the substituents for the aryl and heteroarylgroups forming part of W may be selected from halo (fluoro, chloro,bromo or iodo), C₁₋₄ alkyl, C₁₋₄ alkylsulfanyl, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulphonyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, cyano, nitro,amino, C₁₋₄ alkylamino, C₂₋₄ alkenylamino, di-C₁₋₄ alkylamino, C₁₋₄acylamino, phenyl, phenylamino, benzoylamino, benzylamino, phenylamido,carboxy, C₁₋₄ alkoxycarbonyl or phenyl-C₁₋₁₀ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ carbamoyl, di-C₁₋₄ carbamoyl or any of the above in which ahydrocarbyl moiety is itself substituted by halo, cyano, hydroxy, C₁₋₂alkoxy, amino, nitro, carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl.

More particularly, the substituents for the aryl and heteroaryl groupsforming part of W may be selected from halo (fluoro, chloro, bromo oriodo), C₁₋₄ alkyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, cyano, amino,C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, C₁₋₄ acylamino, carboxy, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ carbamoyl, di-C₁₋₄ carbamoyl or anyof the above substituents in which a hydrocarbyl moiety is itselfsubstituted by halo, cyano, hydroxy, C₁₋₂ alkoxy, amino, nitro,carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl.

In a particular embodiment, the substituents for the aryl and heteroarylgroups forming part of W may be selected from fluoro, chloro, bromo,C₁₋₃ alkyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, cyano, amino, C₁₋₂alkylamino, di-C₁₋₂ alkylamino, C₁₋₂ acylamino, carboxy, C₁₋₂alkoxycarbonyl, carbamoyl, mono-C₁₋₂ carbamoyl, di-C₁₋₂ carbamoyl or anyof the above substituents in which a hydrocarbyl moiety is itselfsubstituted by one or more fluorine atoms or by cyano, hydroxy, C₁₋₂alkoxy, amino, carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl.

In a more particular embodiment, the substituents for the aryl andheteroaryl groups forming part of W may be selected from fluoro, chloro,bromo, cyano, C₁₋₃ alkyl and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl andC₁₋₃ alkoxy moieties are each optionally substituted with one or morefluorine atoms.

The moiety W comprises one or more carbon atoms in the form of a ringstructure. In particular examples, W is a formula of

wherein R′ and R″ are independently H or alkyl (e.g. C₁₋₂ alkyl, morepreferably methyl) and R′″ is an optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl or optionallysubstituted heterocycloalkyl group. R′ may be methyl. R″ may be methyl.

The optional substituents may consist of one or more halo, alkyl oralkoxy groups, or may be selected from the list of optional substituentsshown below. The R′″ group may comprise a substituted aryl or heteroarylgroup. In a 6-membered aromatic ring the substituents may be located atthe 2, 3, 4, 5 or 6 positions. The aryl or heteroaryl group may compriseone, two, three, four or more substituents. The aryl group may bedisubstituted, with the substitutions at any two of positions 2 to 6.The aryl group may be a 2,3-disubstituted, 2,4-disubstituted,2,5-disubstituted, 2,6-disubstituted, 3,4-disubstituted or3,5-disubstituted aryl group. Examples of disubstituted aryl groupsinclude 2-fluoro-6-chloro or 2-chloro-4-fluoro. In the case of alkoxygroups, the groups may be linked together to form a further ring, forexample a 2,3 or 3,4 cyclic acetal group of type O—CH₂—O. The aryl groupmay comprise a 2, 3 or 4 methoxy group. The aryl group may comprise afluoro, chloro, bromo, methyl or cyano group, which may be at the 2, 3or 4 position. The substituents may be acyl groups of type CO-alkyl oracyl esters of type —CO—O— alkyl, for example —CO₂CH₃. The substituentsmay be primary, secondary or tertiary amide groups of type CO—NH₂,CO—NH-alkyl or CO—N(alkyl)₂. In particular the aryl group may be a2,4-disubstituted, 2,6-disubstituted or 2,4,6-trisubstituted aryl group.

The R′″ group may comprise an optionally substituted cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl group.

The R′″ group may be a heteroaryl group, for example 2, 3 or 4 pyridyl.The heteroaryl group may optionally be further substituted, for example2-fluoro,4-pyridyl or disubstituted, for example 2,6-difluoro,4-pyridyl.The heteroaryl group may be 3, 4, 5, 6 or 7 membered, and contain one ormore heteroatoms. The heteroaryl group may be a 5 membered ringcontaining two or more heteroatoms. The heteroatoms may be independentlynitrogen, oxygen or sulphur. The heteroaryl group may be furthersubstituted with one or more rings, which may be linked onto one or morepositions of the heteroaryl group, for example to form a bicyclicheteroaryl group selected from the definitions of heteroaryl foundherein.

In certain examples, W may be selected from one of the following groups

In embodiments in which Y₁ is a nitrogen atom, or where X comprises anoptionally substituted heteroaryl or optionally substitutedheterocycloalkyl moiety, W can be selected from the list above.

In embodiments in which Y₁ is a carbon atom, or where X comprises anoptionally substituted aryl or optionally substituted cycloalkyl group,W may be selected from one of the following groups:

In particular aspects, compounds of the invention may be exemplifiedherein based around the structure:

in which any of Y₁, Y₂, Y₃, Y₄, are independently carbon atoms ornitrogen atoms. The carbon atoms Y₁, Y₂, Y₃, Y₄, may be furthersubstituted, for example with halo groups (fluoro, chloro, bromo oriodo), hydroxyl groups, alkyl groups or substituted alkyl groups,alkenyl or alkynyl groups or alkoxy groups. For example any of Y₁, Y₂,Y₃, Y₄ may be independently N, C—H, C—F, C—Cl, C—Br, C—I, C-alkyl orC—OH. Preferably, no more than one of Y₁, Y₂, Y₃ and Y₄ is N. The alkylgroups may be for example methyl, ethyl, propyl or any other alkyl groupas defined under the definitions of alkyl groups found herein. Thealkyl, alkenyl or alkynyl group may contain 1-4 carbon atoms. The alkylgroup may be cyclic groups such as cyclopropyl or cyclobutyl. R′ and R″are independently H or alkyl. Y₅, Y₆, and Y₇ are each independentlysubstituted carbon atoms or heteroatoms. For example each of Y₅, Y₆, andY₇ may be independently N, C—F, C—Cl, C—Br, C—I, C-alkyl, C—O-alkyl orC—OH. X comprises an optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, or optionally substitutedheterocycloalkyl moiety.

X comprises an optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, or optionally substitutedheterocycloalkyl moiety which may either be attached directly to thethiadiazinone ring or attached through an alkylene linker group. Thealkylene linker group, when present, may have a chain length (extendingbetween the thiadiazinone ring and the cyclic moiety) of up to 3 carbonatoms, one or more of which may optionally bear an alkyl side chain. Thealkylene linker group, when present, typically contains a maximum of 6carbon atoms.

The moiety X comprises one or more carbon atoms in the form of a ringstructure. In particular examples, X may comprise an optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl or optionally substituted heterocycloalkyl group.As indicated above, the optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl or optionallysubstituted heterocycloalkyl group may be connected directly to thenitrogen atom, or may have one or more intervening aliphatic carbonatoms. The intervening carbon atoms may be in the form of a CH₂, CH₂CH₂or CH(alkyl)-group. For example therefore, an aryl group at position Xmay therefore be in the form of N-aryl, or N—CH₂-aryl (benzyl) orN—CH₂CH₂-aryl etc, and the term ‘comprising’ an optionally substitutedaryl, optionally substituted cycloalkyl, optionally substitutedheteroaryl or optionally substituted heterocycloalkyl group includes theoptional aliphatic groups as well as the directly attached rings.

The optional substituents may be selected from the list of optionalsubstituents shown below.

In one general embodiment, the substituents for the optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted heterocycloalkylmoiety forming part of X may be selected from halo (fluoro, chloro,bromo or iodo), oxo, C₁₋₄ alkyl, C₁₋₄ alkylsulfanyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulphonyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄ alkoxy, cyano,nitro, amino, C₁₋₄ alkylamino, C₂₋₄ alkenylamino, di-C₁₋₄ alkylamino,C₁₋₄ acylamino, phenyl, phenylamino, benzoylamino, benzylamino,phenylamido, carboxy, C₁₋₄ alkoxycarbonyl or phenyl-C₁₋₁₀alkoxy)carbonyl, carbamoyl, mono-C₁₋₄ carbamoyl, di-C₁₋₄ carbamoyl orany of the above in which a hydrocarbyl moiety is itself substituted byhalo, cyano, hydroxy, C₁₋₂ alkoxy, amino, nitro, carbamoyl, carboxy orC₁₋₂ alkoxycarbonyl.

More particularly, the substituents for the optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl, oroptionally substituted heterocycloalkyl moiety forming part of X may beselected from halo (fluoro, chloro, bromo or iodo), oxo, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkylsulfanyl, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulphonyl, hydroxy, C₁₋₄ alkoxy, cyano, amino, C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, C₁₋₄ acylamino, carboxy, C₁₋₄ alkoxycarbonyl,carbamoyl, mono-C₁₋₄ carbamoyl, di-C₁₋₄ carbamoyl or any of the abovesubstituents in which a hydrocarbyl moiety is itself substituted byhalo, cyano, hydroxy, C₁₋₂ alkoxy, amino, nitro, carbamoyl, carboxy orC₁₋₂ alkoxycarbonyl.

In a particular embodiment, the substituents for the optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted heterocycloalkylmoiety forming part of X may be selected from fluoro, chloro, bromo,oxo, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkylsulfanyl, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulphonyl, hydroxy, C₁₋₃ alkoxy, cyano, amino,C₁₋₂ alkylamino, di-C₁₋₂ alkylamino, C₁₋₂ acylamino, carboxy, C₁₋₂alkoxycarbonyl, carbamoyl, mono-C₁₋₂ carbamoyl, di-C₁₋₂ carbamoyl or anyof the above substituents in which a hydrocarbyl moiety is itselfsubstituted by one or more fluorine atoms or by cyano, hydroxy, C₁₋₂alkoxy, amino, carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl.

In a more particular embodiment, the substituents for the optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted heterocycloalkylmoiety forming part of X, may be selected from fluoro, chloro, bromo,oxo, C₁₋₃ alkyl, C₁₋₃ alkylsulfanyl, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulphonyl, hydroxy, C₁₋₃ alkoxy, cyano, amino, C₁₋₂ alkylamino anddi-C₁₋₂ alkylamino.

In another more particular embodiment, the substituents for theoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, or optionally substitutedheterocycloalkyl moiety forming part of X, may be selected from oxo,C₁₋₃ alkyl, C₁₋₃ alkylsulfanyl, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulphonyl,hydroxy, C₁₋₃ alkoxy and di-C₁₋₂ alkylamino.

In a further embodiment, the substituents may consist of one or morehalo, alkyl or alkoxy groups.

The moiety X may comprise a substituted aryl or heteroaryl group. Whenthe aryl or heteroaryl group is 6-membered, the substituents may belocated at the 2, 3, 4, 5 or 6 positions. The aryl or heteroaryl groupmay comprise one, two, three, four or more substituents as definedherein, and more particularly may comprise one, two or threesubstituents. The aryl group may be disubstituted, with thesubstitutions at any two of positions 2-6. The aryl group may be a2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted,2,6-disubstituted, 3,4-disubstituted or 3,5-disubstituted aryl group.Examples of disubstituted aryl groups include 3,4-dimethoxy,3,5-dimethoxy, 3,4-dimethyl and 3,5-dimethyl, 3-fluoro,4-cyano and3-fluoro,4-methyl. In the case of alkoxy groups, the groups may belinked together to form a further ring, for example a 2,3 or 3,4 cyclicacetal group of type O—CH₂—O. The aryl group may comprise a 2, 3 or 4methoxy group, ethoxy group or thio-alkyl group. The alkoxy orthio-alkoxy groups may be further substituted, for example to make O—CF₃or S—CF₃ groups. The aryl group may comprise a fluoro, chloro, bromo,methyl, ethyl or cyano group, which may be at the 2, 3 or 4 position.The substituents may be acyl groups of type CO-alkyl or acyl esters oftype —CO—O-alkyl, for example —CO₂CH₃. The substituents may be primary,secondary or tertiary amide groups of type CO—NH₂, CO—NH-alkyl orCO—N(alkyl)₂. The aryl group may be a trisubstituted aryl group, forexample a 3,4,5-trisubstituted aryl group.

The X group may comprise an optionally substituted cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl group. The cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl group may be attached directly tothe nitrogen atom, or may comprise one or more CH₂ or CH(alkyl) groups.

In certain examples X may be of the following structure

The X group may comprise an optionally substituted heterocycloalkylgroup. The heterocycloalkyl group may comprise a cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl group comprising one or moreheteroatoms. The heterocyclopropyl, heterocyclobutyl, heterocyclopentylor heterocyclohexyl group may be attached directly to the nitrogen atom,or may comprise one or more CH₂ or CH(alkyl) groups. The heteroatoms maybe oxygen, nitrogen or sulphur.

The X group may be a heteroaryl group, for example 2, 3 or 4 pyridyl, or2 or 3 pyrryl. The heterocycle group may optionally be furthersubstituted, for example 2-fluoro,4-pyridyl or disubstituted, forexample 2,6-difluoro, 4-pyridyl. The heteroaryl group may be 3, 4, 5, 6or 7 membered, and contain one or more heteroatoms. The heteroaryl groupmay be a 5 or 6 membered ring containing two or more heteroatoms. Theheteroatoms may be independently nitrogen, oxygen or sulphur, and theheteroatoms may be further optionally substituted. The heteroaryl groupmay comprise, for example, a N-substituted triazole moiety or anN-substituted imidazoyl moiety. The heteroaryl group may comprise one ormore further rings, which may have aromatic conjugation. For example Xmay be a benzothiazolyl, indazolyl or quinolinyl group.

In certain Examples X may be of the following structure

In certain embodiments, in which Y₁ is a nitrogen atom, or in which Wcomprises a 2,4,6-tri-substituted benzylic group or is an optionallysubstituted heteroaryl or optionally substituted heterocycloalkylmoiety, X can be selected from the following list.

In particular aspects, compounds of the invention may be exemplifiedherein based around the structure:

In which any of Y₁, Y₂, Y₃, Y₄, are independently carbon atoms orheteroatoms. The carbon atoms Y₁, Y₂, Y₃, Y₄, may be furthersubstituted, for example with halo groups (fluoro, chloro, bromo oriodo), hydroxyl groups, alkyl groups or substituted alkyl groups,alkenyl or alkynyl groups or alkoxy groups. For example any of Y₁, Y₂,Y₃, Y₄ may be independently N, C—H, C—F, C—Cl, C—Br, C—I, C-alkyl orC—OH. Preferably, no more than one of Y₁, Y₂, Y₃ and Y₄ is N The alkylgroups may be for example methyl, ethyl, propyl or any other alkyl groupas defined under the definitions of alkyl groups found herein. Thealkyl, alkenyl or alkynyl group may contain 1-4 carbon atoms. The alkylgroup may be cyclic groups such as cyclopropyl or cyclobutyl. R′ and R″are independently H or alkyl. R′″ is a substituted aryl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl or optionallysubstituted heterocycloalkyl group. X comprises an optionallysubstituted heteroaryl, or optionally substituted heterocycloalkylmoiety.

In particular aspects, compounds of the invention may be exemplifiedherein based around the structure:

In which any of Y₁, Y₂, Y₃, Y₄, are independently carbon atoms orheteroatoms. The carbon atoms Y₁, Y₂, Y₃, Y₄, may be furthersubstituted, for example with halo groups (fluoro, chloro, bromo oriodo), hydroxyl groups, alkyl groups or substituted alkyl groups,alkenyl or alkynyl groups or alkoxy groups. For example any of Y₁, Y₂,Y₃, Y₄ may be independently N, C—H, C—F, C—Cl, C—Br, C—I, C-alkyl orC—OH. The alkyl groups may be for example methyl, ethyl, propyl or anyother alkyl group as defined under the definitions of alkyl groups foundherein. The alkyl, alkenyl or alkynyl group may contain 1-4 carbonatoms. The alkyl group may be cyclic groups such as cyclopropyl orcyclobutyl. R′ and R″ are independently H or alkyl. R′″ is a substitutedaryl, optionally substituted cycloalkyl, optionally substitutedheteroaryl or optionally substituted heterocycloalkyl group. Y₅, Y₆, Y₇,Y₈, and Y₉ are independently carbon atoms or heteroatoms. The carbonatoms Y₅, Y₆, Y₇, Y₈, and Y₉ may be further substituted, for examplewith halo groups (fluoro, chloro, bromo or iodo), hydroxyl groups, alkylgroups or substituted alkyl groups, alkenyl or alkynyl groups, amino oralkoxy groups. For example any of Y₅, Y₆, Y₇, Y₈, and Y₉ may beindependently N, C—H, C—F, C—Cl, C—Br, C—I, C-Me, C—OMe, C—NH₂, CNH-Me,C—N(Me)₂ or C—OH. Compounds where Y₈ is N, C-Me, C—OMe or C—N(Me)₂ showhigh affinity as orexin receptor binders and may be preferred.

In one embodiment, there is provided a compound as hereinbefore defined,or a salt thereof;

wherein

Y¹ is CH, C-halo or N, where halo is a halogen atom;

Y² is CH;

Y³ is CH or N, provided that no more than one of Y¹ and Y³ may be N;

Y⁴ is CH;

W is a methylene group substituted with a phenyl, pyridyl or pyrazolegroup, wherein the pyrazole or pyridyl groups are each optionallysubstituted with one or more C₁₋₄ alkyl groups, and the phenyl group issubstituted with one or more substituents selected from halogen, C₁₋₄alkyl and C₁₋₄ alkoxy;andX is selected from:

-   -   phenyl, pyridyl and pyridylmethyl, the aromatic rings of which        in each case are optionally substituted with one or more        substituents selected from C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy,        C₁₋₄ alkylsulphanyl, C₁₋₄ alkylsulphanonyl and di-C₁₋₄        alkylamino;    -   a group —(CH₂)_(q)—Cyc wherein q is 0, 1 or 2 and Cyc is a group        selected from imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,        thiazolyl, oxazolyl, piperidinyl, pyrrolidinyl, azetidinyl,        tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, indazolyl,        benzothiazolyl, wherein each of the Cyc groups is optionally        substituted with one or more methyl groups;    -   1-methyl-6-oxo-1,6-dihydropyridine;    -   methoxyprimidinyl; and    -   2-oxo-1,2-dihydroquinolinylmethyl;        provided that:        (i) at least one of Y₁ and Y₃ is nitrogen; and/or (ii) X is a        group —(CH₂)_(q)—Cyc; and/or        (iii) when W is a methylene group substituted with a phenyl        group, the phenyl group is a 2,4,6-trisubstituted phenyl group.

In another embodiment, there is provided a compound as hereinbeforedefined, or a salt thereof;

wherein

Y¹ is CH, CF or N;

Y² is CH;

Y³ is CH or N, provided that no more than one of Y¹ and Y³ may be N;

Y⁴ is CH;

W is a methylene group substituted with a moiety selected from:

-   -   a phenyl group substituted with one or more substituents        selected from fluorine, chlorine, methyl and methoxy;    -   a pyridyl group substituted with one or more substituents        selected from fluorine, chlorine, bromine and methyl; and    -   a dimethylpyrazole group;        and        X is selected from:    -   phenyl substituted with one or more substituents selected from        methyl, hydroxy, methoxy, methylsulphanyl and methylsulphonyl;    -   pyridyl substituted with one or more substituents selected from        methyl, methoxy, methylsulphanyl, hydroxy and dimethylamino;    -   pyridylmethyl wherein the pyridyl moiety is optionally        substituted with one or more methoxy groups;    -   benzothiazolyl;    -   ethylpyrazolyl;    -   methoxyprimidinyl;    -   ethylpiperidinyl;    -   1-methyl-1H-indazol-3-yl;    -   dimethylisoxazolylethyl;    -   dimethylpyrazolylmethyl;    -   tetrahydropyranylmethyl;    -   methyloxetanylmethyl;    -   methylthiazolylmethyl;    -   methylisoxazolylmethyl;    -   methylimidazolylmethyl;    -   2-oxo-1,2-dihydroquinolinylmethyl;        provided that:        (i) at least one of Y₁ and Y₃ is nitrogen; and/or (ii) X is        other than a substituted phenyl group; and/or (iii) when W is a        methylene group substituted with a phenyl group, the phenyl        group is a 2,4,6-trisubstituted phenyl group.

Certain compounds have been produced in the prior art for medical uses.In particular examples, compounds where X is a cyclopropyl group havebeen reported. Examples of known compounds include:

Any medical uses of the compounds described herein may disclaim specificexamples where X is a cyclopropyl group.

The following compounds are known, but have not been associated with aparticular medical use. In all cases the compounds do not contain asubstituted aryl group at position W. In all cases, the compounds do notdisclose where Y₄ is CH, or where Y₄ is N.

2H-1,2,4-Benzothiadiazin-3(4H)-one,6,8-dichloro-2-[(5-methyl-2-furanyl)methyl]-4-(phenylmethyl)-,1,1-dioxide

2H-1,2,4-Benzothiadiazin-3(4H)-one,6,8-dichloro-4-(phenylmethyl)-2-(4-pyridinylmethyl)-,1,1-dioxide

Any of the features of W, X and Y₁-Y₉ defined herein may be combinedwith any of the other features of W, X and Y. Thus, for example, Y₁ mayor may not comprise a heteroatom and X may or may not be a heterocyclicgroup, and thus all combinations of Y₁ is and is not a heteroatom, and Xis and is not a heterocycle are envisaged. In certain combinations,compounds will be novel.

Certain specific examples of compounds are shown below. Each of thecompounds shown below is either novel by way of structure, or novel byway of medical use, particularly its medical use as an orexin receptorantagonist.

Further embodiments of the invention include methods of treatmentcomprising administering a compound of formula

wherein Y₁, Y₂, Y₃ are independently an optionally substituted carbon ora nitrogen atom; and Y₄ is is C-alkyl, C-halogen, C—H or N,W is amethylene group or CH(alkyl) group substituted by an optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl or optionally substituted heteroaryl moietyand X comprises an optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, or optionally substitutedheterocycloalkyl moiety, wherein X is not cyclopropyl.

The methods of treatment may be used in treating, preventing,ameliorating, controlling or reducing the risk of neurological orpsychiatric disorders associated with orexin receptors, for exampleinsomnia, diabetes, obesity, the treatment or prevention of substancedependence, addiction, movement disorders, anxiety disorders, panicdisorders, cognitive impairment or Alzheimer's disease.

The methods of treatment will typically involve the administration of atherapeutically effective amount (preferably a non-toxic amount) of thecompound to a subject (e.g. a mammalian subject such as a human) in needthereof.

The following compounds in list 1 are novel in their own right, anduseful in treating certain medical conditions, for example conditionsinvolving orexin receptors.

List 1

Compounds 83-186 from Table 1

The following compounds in list 2 are useful in treating certain medicalconditions, for example conditions involving orexin receptors.

List 2

Compounds 1-82 from Table 1

Certain novel compounds of the invention show particularly highactivities as orexin antagonists; for example

-   2-(3,4-Dimethoxyphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 93-   4-(4-Chloro-2,6-difluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 97-   2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 98-   2-(5,6-Dimethoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 99-   2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 100-   2-(3,4-Dimethoxyphenyl)-4-(2,6-difluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 108-   4-(2-Chloro-6-fluoro-4-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 113-   2-(4-methoxy-3,5-dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 115-   4-(2,6-Difluoro-4-hydroxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 116-   4-(2,6-Difluoro-4-methoxybenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 140-   2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 145-   4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-Dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 146-   2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 148-   4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 149-   4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 155-   4-(2-Chloro-4,6-difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 157-   2-[6-(Dimethylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 158-   2-[2-(Dimethylamino)pyridin-4-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 159-   4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 163-   4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 164-   4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 165-   4-(2-Chloro-6-fluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 166-   4-(2,6-Difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 167-   4-(2-Chloro-6-fluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 168-   4-(2,-Difluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 169-   2-(4,5-dimethoxypyrimidin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 170-   4-(2,6-difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 171-   2-[6-methoxy-5-(methylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 172-   4-(2,6-difluoro-4-methoxybenzyl)-2-(5,    6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 173-   4-(2,6-difluoro-4-methoxybenzyl)-2-(4,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 174-   4-(2,6-difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 175-   2-(5-methoxy-6-methylpyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 176-   4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 177-   4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 178-   4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-2-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 179-   4-(2-chloro-4,6-difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 180-   4-(2,6-difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 181-   4-(2,6-difluoro-4-methoxybenzyl)-2-(4,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one    1,1-dioxide 183-   4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methyl-6-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 184-   4-(2-chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 185-   4-(2,6-difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one    1,1-dioxide 186

To the extent that any of the compounds described have chiral centres,the present invention extends to all optical isomers of such compounds,whether in the form of racemates or resolved enantiomers. The inventiondescribed herein relates to all crystal forms, solvates and hydrates ofany of the disclosed compounds however so prepared. To the extent thatany of the compounds disclosed herein have acid or basic centres such ascarboxylates or amino groups, then all salt forms of said compounds areincluded herein. In the case of pharmaceutical uses, the salt should beseen as being a pharmaceutically acceptable salt.

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound with one or more equivalents of an appropriateacid or base, optionally in a solvent, or in a medium in which the saltis insoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound inthe form of a salt with another counter-ion, for example using asuitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals such as sodium, magnesium, or preferably, potassium andcalcium.

Examples of acid addition salts include acid addition salts formed withacetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g.benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic andp-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic,4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic,(+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic,citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric,gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g.D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic,hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g.(+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g.(−)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic,4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic,tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valericacids.

Particular examples of salts are salts derived from mineral acids suchas hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acids; from organic acids, such as tartaric, acetic, citric,malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic,arylsulfonic acids; and from metals such as sodium, magnesium, orpreferably, potassium and calcium.

Also encompassed are any solvates of the compounds and their salts.Preferred solvates are solvates formed by the incorporation into thesolid state structure (e.g. crystal structure) of the compounds of theinvention of molecules of a non-toxic pharmaceutically acceptablesolvent (referred to below as the solvating solvent). Examples of suchsolvents include water, alcohols (such as ethanol, isopropanol andbutanol) and dimethylsulfoxide. Solvates can be prepared byrecrystallising the compounds of the invention with a solvent or mixtureof solvents containing the solvating solvent. Whether or not a solvatehas been formed in any given instance can be determined by subjectingcrystals of the compound to analysis using well known and standardtechniques such as thermogravimetric analysis (TGE), differentialscanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates may be hydrates, and examples of hydrates includehemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

“Pharmaceutically functional derivatives” of compounds as defined hereinincludes ester derivatives and/or derivatives that have, or provide for,the same biological function and/or activity as any relevant compound ofthe invention. Thus, for the purposes of this invention, the term alsoincludes prodrugs of compounds as defined herein.

The term “prodrug” of a relevant compound includes any compound that,following oral or parenteral administration, is metabolised in vivo toform that compound in an experimentally-detectable amount, and within apredetermined time (e.g. within a dosing interval of between 6 and 24hours (i.e. once to four times daily)).

Prodrugs of compounds may be prepared by modifying functional groupspresent on the compound in such a way that the modifications arecleaved, in vivo when such prodrug is administered to a mammaliansubject. The modifications typically are achieved by synthesizing theparent compound with a prodrug substituent. Prodrugs include compoundswherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in acompound is bonded to any group that may be cleaved in vivo toregenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonylgroup, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxyl functional groups, esters groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elsevier, New York-Oxford (1985).

DEFINITIONS Alkyl

Alkyl means an aliphatic hydrocarbon group. The alkyl group may bestraight or branched. “Branched” means that at least one carbon branchpoint is present in the group. Thus, for example, tert-butyl andisopropyl are both branched groups. The alkyl group may be a lower alkylgroup. “Lower alkyl” means an alkyl group, straight or branched, having1 to about 6 carbon atoms, e.g. 2, 3, 4, 5 or 6 carbon atoms.

Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, s-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl,2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl,2-methyl-but-1-yl, 2-methyl-but-3-yl, 2-methyl-pent-1-yl,2-methyl-pent-3-yl.

The alkyl group may be optionally substituted, e.g. as exemplifiedbelow.

The term alkyl also includes aliphatic hydrocarbon groups such asalkenyl, and alkylidene.

Alkenyl

Alkenyl means an unsaturated aliphatic hydrocarbon group. Theunsaturation may include one or more double bond, one or more triplebond or any combination thereof. The alkenyl group may be straight orbranched. “Branched” means that at least one carbon branch point ispresent in the group. Any double bond may, independently of any otherdouble bond in the group, be in either the (E) or the (Z) configuration.

The alkenyl group may be a lower alkenyl group. “Lower alkenyl” means analkenyl group, straight or branched, having 2 to 6 carbon atoms, e.g. 2,3, 4, 5 or 6 carbon atoms.

Exemplary alkenyl groups include ethenyl, n-propenyl, i-propenyl,but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, pent-1-en-1-yl,pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, pent-1-en-2-yl,pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1-en-3-yl,pent-2-en-3-yl, pentadien-1-yl, pentadien-2-yl, pentadien-3-yl. Wherealternative (E) and (Z) forms are possible, each is to be considered asindividually identified.

The alkenyl group may be optionally substituted, e.g. as exemplifiedbelow.

Alkylidene

Alkylidene means any alkyl or alkenyl group linked to the remainder ofthe molecule via a double bond. The definitions and illustrationsprovided herein for alkyl and alkenyl groups apply with appropriatemodification also to alkylidene groups.

Cycloalkyl

Cycloalkyl means a cyclic non-aromatic hydrocarbon group. The cycloalkylgroup may include non-aromatic unsaturation. The cycloalkyl group mayhave 3 to 6 carbon atoms, e.g. 3, 4, 5 or 6 carbon atoms. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentenyl, cyclohexenyl.

The cycloalkyl group may be optionally substituted, as defined below,e.g. as exemplified below. Exemplary substituted cycloalkyl groupsinclude mono- or poly-alkyl-substituted cycloalkyl groups such as1-methylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclopentyl,1-methylcyclohexyl, 2-methylcyclopropyl, 2-methylcyclobutyl,2-methylcyclopentyl, 2-methylcyclohexyl, 1,2-dimethylcyclohexyl or1,3-dimethylcyclohexyl.

Cycloalkylidene Group

Cycloalkylidene means any cycloalkyl group linked to the remainder ofthe molecule via a double bond. The definitions and illustrationsprovided herein for cycloalkyl groups apply with appropriatemodification also to cycloalkylidene groups.

Aryl

Aryl means any aromatic group in which all of the ring members arecarbon atoms, for example having up to 12 carbon atom ring members, e.g.6, 7, 8, 9, 10, 11 or 12 carbon atom ring members. The aryl group maycomprise one, two or more rings. Where two or more rings are presentthey may if desired be fused. The aryl groups may be optionallysubstituted further, as described below. The aryl group may comprise oneor more phenyl ring. The point of attachment of aryl groups may be viaany atom of the ring system.

Exemplary aryl groups include phenyl, naphthyl, tetrahydronaphthyl,biphenyl, indanyl and dihydroindanyl groups. The point of attachment maybe via any atom of the ring system.

Heteroaryl

Heteroaryl means an aromatic group in which at least one ring member isother than carbon. For example, at least one ring member (for exampleone, two or three ring members) may be selected from nitrogen, oxygenand sulphur.

The heteroaryl group may comprise one, two or more rings. Where two ormore rings are present they may if desired be fused. The heteroarylgroups may be optionally substituted further, as described below. Whenthe heteroaryl group contains more than one ring, a second and/or thirdring may be heteroaromaic or may be a phenyl ring. The point ofattachment of heteroaryl groups may be via any atom of the ring system.

Exemplary heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl,furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, indolyl, indolizinyl,isoindolyl, indolinyl, purinyl, furazanyl, imidazolyl, indazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxazinanyl, 1,3-oxazinanyl,pyrazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, benzofuranyl, isobenzofuranyl,benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl,napthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl andthe like. The point of attachment may be via any atom of the ringsystem.

Heterocycloalkyl

Heterocycloalkyl group means a non-aromatic cyclic group which containsone or more heteroatoms in the ring. The heterocycloalkyl group maycontain O, N or S atoms. The heterocycloalkyl group may be fullysaturated or partially unsaturated. The heterocycloalkyl group istypically monocyclic or bicyclic, and more usually is monocyclic.

Exemplary heterocycloalkyl groups include azetidinyl, pyrrolidinyl,piperidinyl, azepinyl, diazepinyl, dihydrofuranyl (e.g.2,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido,dioxolanyl, 2-imidazolinyl, imidazolidinyl, isoxazolidinyl, morpholinyl,oxazolidinyl, piperazinyl, pyrrolidinonyl, 2-pyrrolinyl, 3-pyrrolinyl,sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, thiomorpholinyl,dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), dioxanyl,hexahydropyrimidinyl, 2-pyrazolinyl, pyrazolidinyl, pyridazinyl,4H-quinolizinyl, quinuclinyl, tetrahydropyranyl,3,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl,3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl,tetramethylenesulfoxide, thiazolidinyl, 1,3,5-triazinanyl,1,2,4-triazinanyl, hydantoinyl, and the like. The point of attachmentmay be via any atom of the ring system.

Heterocycloalkylidene Group

Heterocycloalkylidene means any heterocycloalkyl group linked to theremainder of the molecule via a double bond. The definitions andillustrations provided herein for heterocycloalkyl groups apply withappropriate modification also to heterocycloalkylidene groups.

Optionally Substituted

“Optionally substituted” as applied to any group means that the saidgroup may if desired be substituted with one or more substituents, whichmay be the same or different.

Examples of suitable substituents for “substituted” and “optionallysubstituted” moieties include halo (fluoro, chloro, bromo or iodo), C₁₋₆alkyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₆ alkoxy, cyano, amino, nitro, C₁₋₆alkylamino, C₂₋₆ alkenylamino, di-C₁₋₆ alkylamino, C₁₋₆ acylamino,di-C₁₋₆ acylamino, C₁₋₆ aryl, C₁₋₆ arylamino, C₁₋₆ aroylamino,benzylamino, C₁₋₆ arylamido, carboxy, C₁₋₅ alkoxycarbonyl or (C₁₋₆aryl)(C₁₋₁₀ alkoxy)carbonyl, carbamoyl, mono-C₁₋₆ carbamoyl, di-C₁₋₆carbamoyl or any of the above in which a hydrocarbyl moiety is itselfsubstituted by halo, cyano, hydroxy, C₁₋₂ alkoxy, amino, nitro,carbamoyl, carboxy or C₁₋₂ alkoxycarbonyl. In groups containing anoxygen atom such as hydroxy and alkoxy, the oxygen atom can be replacedwith sulphur to make groups such as thio (SH) and thio-alkyl (S-alkyl).Optional substituents therefore includes groups such as S-methyl. Inthio-alkyl groups, the sulphur atom may be further oxidised to make asulfoxide or sulfone, and thus optional substituents therefore includesgroups such as S(O)-alkyl and S(O)₂-alkyl.

Substituted groups thus include for example CN, CFH₂, CF₂H, CF₃, CH₂NH₂,CH₂OH, CH₂CN, CH₂SCH₃, CH₂OCH₃, OMe, OEt, Me, Et, —OCH₂O—, CO₂Me,C(O)Me, i-Pr, SCF₃, SO₂Me, NMe₂ etc. In the case of aryl groups, thesubstitutions may be in the form of rings from adjacent carbon atoms inthe aryl ring, for example cyclic acetals such as O—CH₂—O.

“Acyl” means an H—CO— or C₁₋₁₀ alkyl-CO— group wherein the alkyl groupis as defined herein. Exemplary acyl groups include formyl, acetyl,propanoyl, 2-methylpropanoyl and butanoyl.

The term “pharmaceutical composition” in the context of this inventionmeans a composition comprising an active agent and comprisingadditionally one or more pharmaceutically acceptable carriers. Thecomposition may further contain ingredients selected from, for example,diluents, adjuvants, excipients, vehicles, preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavouring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispersing agents, depending on the nature of the mode of administrationand dosage forms. The compositions may take the form, for example, oftablets, dragees, powders, elixirs, syrups, liquid preparationsincluding suspensions, sprays, inhalants, tablets, lozenges, emulsions,solutions, cachets, granules, capsules and suppositories, as well asliquid preparations for injections, including liposome preparations.

The dosages may be varied depending upon the requirements of thepatient, the seventy of the condition being treated, and the compoundbeing employed.

Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with the smallerdosages which are less than the optimum dose of the compound. Thereafterthe dosage is increased by small increments until the optimum effectunder the circumstances is reached. For convenience, the total dailydosage may be divided and administered in portions during the day ifdesired.

The magnitude of an effective dose of a compound will, of course, varywith the nature of the severity of the condition to be treated and withthe particular compound and its route of administration. The selectionof appropriate dosages is within the ability of one of ordinary skill inthis art, without undue burden. In general, the daily dose range may befrom about 10 μg to about 30 mg per kg body weight of a human andnon-human animal, preferably from about 50 μg to about 30 mg per kg ofbody weight of a human and non-human animal, for example from about 50μg to about 10 mg per kg of body weight of a human and non-human animal,for example from about 100 μg to about 30 mg per kg of body weight of ahuman and non-human animal, for example from about 100 μg to about 10 mgper kg of body weight of a human and non-human animal and mostpreferably from about 100 μg to about 1 mg per kg of body weight of ahuman and non-human animal.

Preparation of the Compounds of the Invention

Compounds may be prepared via a variety of synthetic routes. A schematicof some of the different routes available is shown in FIG. 1.

Compounds of the invention may be prepared by routes including those inFIG. 1, where in each case the starting aromatic or heteroaromatic ringmay be optionally substituted by groups in addition to those shown.Details of many of the standard transformations such as those in theroutes below and others which could be used to perform the sametransformations can be found in standard reference textbooks such as“Organic Synthesis”, M. B. Smith, McGraw-Hill (1994) or “AdvancedOrganic Chemistry”, 4^(th) edition, J. March, John Wiley & Sons (1992).

Sulphonamide formations (for example Step 1 of Routes 1, 2 and 4, andStep 2 of Route 5) can be achieved by reaction of an amine with anaromatic or heteroaromatic sulfonyl chloride in a suitable solvent suchas 1,4-dioxane, diethyl ether, DCM or 1,2-dichloroethane, in the absenceof a base, or in the presence of base such as triethylamine, pyridine orN,N-diisopropylethylamine. Typically this coupling procedure isconducted at a temperature of between −10° C. and 100° C. Alternatively,(e.g. as described in Trani et al Bioorg. Med. Chem. Lett. 2008, 18,5698) the coupling can be conducted in the presence ofbis(trimethylsilyl)trifluoroacetamide and pyridine in DCM.

Reduction of an aromatic nitro group (for example Route 1, Step 2) canbe performed under reaction conditions known to those skilled in theart; for example catalytic hydrogenation using a catalyst such aspalladium on charcoal, palladium oxide or platinum oxide in a suitablesolvent such as ethanol, water, ethyl acetate or combinations thereofunder an atmosphere of hydrogen. Alternative conditions will be known tothose skilled in the art, for example reduction with tin(II) chloride inethanol, typically at an elevated temperature such as 100° C. or withiron powder and acetic acid, typically at an elevated temperature suchas 60° C.

Intramolecular cyclisation reactions between adjacent aromatic andsulphonamide groups on an aromatic or heteroaromatic ring (such as Route1-4 inclusive, Step 3; Route 5, Step 4 and Route 7, Step 3) can beperformed for example with 1,1′-carbonyldiimidazole and a base such astriethylamine in a suitable solvent such as DMF at elevated temperature,for example 100° C., as described by Hanson et al in Tetrahedron Lett.2009, 50, 6935. Alternative conditions will be known to those skilled inthe art, for example the use of triphosgene in a suitable solvent (e.g.1,4-dioxane) at elevated temperature, for example 100° C.

N-alkylation reactions (for example Route 1, Step 4 and Route 6, Step 3)can be performed under reaction conditions known to those skilled in theart and detailed in standard reference textbooks such as those above.For example S_(N)2 reactions with an alkyl (or benzyl) halide or otherelectrophilic species such as an alkyl (or benzyl) tosylate or mesylate,in the presence of a base (e.g. potassium carbonate or cesium carbonate)in a suitable solvent such as 1,4-dioxane or DMF at a suitabletemperature such as room temperature to 130° C. Alternatively, Mitsunobucoupling conditions (see Mitsunobu, O. Synthesis 1981, 1) using adialkyl azodicarboxylate (such as diethyl azodicarboxylate ordiisopropyl azodicarboxylate) or 1,1′-azobis(N,N-dimethylformamide),triphenylphosphine and an alcohol in a suitable solvent such as THF canbe used for N-alkylation. In some instances, sonication is used to aidsolubility of the reaction mixtures.

Nucleophilic aromatic substitution reactions (S_(N)Ar reactions) (forexample Routes 2-4 inclusive, Step 2 and Route 5, Step 3) are typicallyconducted at elevated temperature (e.g. 100-200° C.), in some instancesin a microwave reactor, in a suitable solvent (e.g. acetonitrile), insome instances with additional base such as triethylamine orN,N-diisopropylethylamine. In some instances (e.g. Route 7, Step 2)autoclave conditions are used.

Sulfonamide N-arylation reactions (for example Route 3, Step 1) arewidely described in the literature, and typically use an aryl halide, apalladium or copper(I) calatyst and a suitable ligand, for example asdescribed in Han, Tetrahedron Lett. 2010, 51, 360.

Chlorination reactions to convert a hydroxy to a chloro substituent inheteroaromatic systems (Route 5, Step 1) and reductive aminationreactions (Route 6, Step 1) can be formed under reaction conditionswhich will be known to those skilled in the art, for example usingphosphorous(V) oxychloride in a suitable solvent such as1,2-dichloroethane.

Cyclisation of a substituted aromatic amine to form a4-substituted-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide ring system(Route 6, Step 1) can be performed using chlorosulfonylisocyanate in asuitable solvent (e.g. nitroethane or nitromethane) at low temperature(e.g. −40° C. to −45° C.); followed by treatment with aluminium chlorideand heating (see for example Tedesco et al, J. Med. Chem. 2006, 49,971).

In the processes described above and hereinafter, the functional groupsof intermediate compounds may need to be protected by protecting groups.The protection and deprotection of functional groups may take placebefore or after a reaction in the below-mentioned schemes. Protectinggroups may be removed in accordance with techniques that are well knownto those skilled in the art and as described hereinafter. For example,protected compounds/intermediates described herein may be convertedchemically to unprotected compounds using standard deprotectiontechniques. The type of chemistry involved will dictate the need, andtype, of protecting groups as well as the sequence for accomplishing thesynthesis. The use of protecting groups is fully described in“Protective Groups in Organic Chemistry”, edited by J. W. F. McOmie,Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 4thedition, T.W. Greene & P.G.M. Wuts, Wiley (2006).

Examples of the invention may be transformed into further examples ofthe invention by modification of substituents, for example an aromaticor heteroaromatic methyl ether may be transformed into an aromatic orheteroaromatic hydroxyl group by removal of the methyl ether understandard conditions (e.g. BBr₃ in DCM at low temperature). In anotherexample an aromatic or heteroaromatic sulphide can be oxidised to anaromatic or heteroaromatic sulfone in the presence of a suitableoxidising agent (for example meta chloroperoxybenzoic acid, KMnO₄,t-butylammoniumperiodate and/or potassium peroxymonosulfate (e.g.Oxone).

Exemplary compounds of the invention, and their corresponding biologicaldata are shown below:

TABLE 1 OX2 ref pKi STRUCTURE number Name ave

1 4-(1,3-benzodioxol-5-ylmethyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.5

2 2-(3,4-dimethoxyphenyl)-4-(3-fluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 6.85

3 2-(3,5-dimethoxyphenyl)-4-(3- methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.35

4 3-{[2-(3,4-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin- 4-yl]methyl}benzonitrile 6.45

5 4-benzyl-2-(3,4-dimethoxyphenyl)-2H- 1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide 7.05

6 2-(3,5-dimethoxyphenyl)-4-(3- methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.33

7 2-(3,4-dimethoxyphenyl)-4-(4- methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.43

8 2-(3,4-dimethoxyphenyl)-4-(4- fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.25

9 4-(3-bromobenzyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.45

10 4-(3-fluoro-4-methoxybenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 6.93

11 2-(3-ethylphenyl)-4-(3-fluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.32

12 4-(3-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.46

13 2-(3,5-dimethoxyphenyl)-4-(2- fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.57

14 4-(2-fluorobenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1- dioxide 6.7

15 2-(3,5-dimethoxyphenyl)-4-(2- methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.53

16 4-(2-chlorobenzyl)-2-(3,5- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.5

17 methyl 3-{[2-(3,5-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazin-4-yl]methyl}-4-methoxybenzoate 7.87

18 2-(3,4-dimethoxyphenyl)-4-(2- methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.83

19 4-(2-chlorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.73

20 4-(2-chloro-6-fluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 9.13

21 4-(2-chloro-4-fluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.63

22 4-(2-chlorobenzyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.63

23 4-(2-fluorobenzyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.68

24 4-(2-chloro-6-fluorobenzyl)-2-(4-chlorophenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.15

25 4-(2-chloro-6-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.6

26 4-(2-chloro-6-fluorobenzyl)-2-phenyl-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.1

27 4-(2-chloro-6-fluorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 9.2

28 4-(2-chloro-6-fluorobenzyl)-2-(4-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.25

29 4-(2-chloro-6-fluorobenzyl)-2-(4-ethoxyphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.5

30 2-(4-acetylphenyl)-4-(2-chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.7

31 4-(2-chloro-6-fluorobenzyl)-2-(3-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.98

32 4-(2-chloro-6-fluorobenzyl)-2-(2,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.55

33 4-(2-chloro-6-fluorobenzyl)-2-(2-ethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.55

34 4-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.95

35 4-(2-chloro-6-fluorobenzyl)-2-(2-methoxyphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.5

36 4-(2-chloro-6-fluorobenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.8

37 4-(2-chloro-6-fluorobenzyl)-2-(4-ethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.3

38 4-(2-chloro-6-fluorobenzyl)-2-(2,3-dimethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.8

39 4-(2-chloro-6-fluorobenzyl)-2-(4-fluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.7

40 2-benzyl-4-(2-chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.58

41 4-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.6

42 4-(2-chloro-6-fluorobenzyl)-2-(3-chlorophenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.85

43 4-(2-chloro-6-fluorobenzyl)-2-(3-fluoro-4-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.33

44 4-(2-chloro-6-fluorobenzyl)-2-(4-fluorophenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.5

45 4-(2-chloro-6-fluorobenzyl)-2-(2,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.78

46 4-(2-chloro-6-fluorobenzyl)-2-(2,5-difluorophenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.2

47 4-(2-chloro-6-fluorobenzyl)-2-(3-ethylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.6

48 4-(2-chloro-6-fluorobenzyl)-2-[4-(propan-2-yl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)- one 1,1-dioxide 8.43

49 4-(2-chloro-6-fluorobenzyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.98

50 4-(2-chloro-4-fluorobenzyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.45

51 4-(2,5-dimethylbenzyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.75

52 methyl 3-({2-[3-(methylsulfanyl)phenyl]-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazin-4-yl}methyl)-4-methoxybenzoate 8.58

53 4-(2-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.5

54 4-(2-methylbenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.36

55 4-(2-chlorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1- dioxide 7.51

56 4-(2-fluorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1- dioxide 7.68

57 4-(2-fluorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1- dioxide 7.63

58 2-benzyl-4-(2-chlorobenzyl)-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 6.03

59 4-(2-chlorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1- dioxide 7.36

60 methyl 3-{[2-(3,4-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazin-4-yl]methyl}-4-methoxybenzoate 7.39

61 4-(Cyclobutylmethyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.57

62 4-(Cyclohexylmethyl)-2-[3- (methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.06

63 7-Fluoro-4-[1-(2-fluorophenyl)ethyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide6.08

64 4-(2-Chloro-6-fluorobenzyl)-2- (cyclohexylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.18

65 4-{[4-(2,6-Difluorobenzyl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl]methyl}-2-fluorobenzonitrile 6.7

66 4-(2,6-Difluorobenzyl)-2-[2-(3- methoxyphenyl)ethyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.26

67 2-(3,4-Dimethoxyphenyl)-4-(2- fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.15

68 4-(2,6-Dichlorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 9.15

69 4-(2-Chloro-6-fluorobenzyl)-2-(3,5- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.97

70 4-(2,6-Dichlorobenzyl)-2-(3,5- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.7

71 4-(3-Chloro-2-fluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.15

72 4-(4-Chloro-2-fluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.98

73 4-(2-Chloro-6-fluorobenzyl)-2-{3-[(trifluoromethyl)sulfanyl]phenyl}-2H- 1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide 8.68

74 4-(2-Chloro-6-fluorobenzyl)-7-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.93

75 4-(2,6-Difluorobenzyl)-2-{3- [(trifluoromethyl)sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.08

76 4-(2-Chloro-6-fluorobenzyl)-6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.83

77 4-(2,6-Dimethylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.05

78 4-(2-Chloro-6-fluorobenzyl)-2-(3,4,5- trimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.39

79 4-(2-Fluoro,6-methylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 9.41

80 4-(2-Chloro-4-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide 8.12

81 4-(2-chloro-6-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide10.08

82 4-(2-Chloro-6-fluorobenzyl)-2-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide 8.48

83 4-[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 6.53

84 2-(3,4-Dimethoxyphenyl)-4-[(2,4-dimethylpyridin-3-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 6.31

85 4-[(3,5-Difluoropyridin-4-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide 7.22

86 4-[(3,5-Dimethylpyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.13

87 4-[(3-Methylpyridin-2-yl)methyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.45

88 2-(3,4-Dimethoxyphenyl)-4-[(3- fluoropyridin-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.55

89 4-[(5-Bromo-3-fluoropyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.41

90 4-[(3,5-Dichloropyridin-4-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.52

91 4-(2-Chloro-6-fluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin- 3(4H)-one 1,1-dioxide 7.42

92 4-(4-Chloro-2-fluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin-3(4H)- one 1,1-dioxide 6.13

93 2-(3,4-Dimethoxyphenyl)-4-(2,4,6- trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)- one 1,1-dioxide 8.92

94 4-(2-Chloro-6-fluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin- 3(4H)-one 1,1-dioxide 9.11

95 4-(2,6-Difluoro-4-methoxybenzyl)-2-(3,4- dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 9.89

96 4-[(3,5-Difluoropyridin-2-yl)methyl]-2- (3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 7.88

97 4-(4-Chloro-2,6-difluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin- 3(4H)-one 1,1-dioxide 9.18

98 2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6- trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.83

99 2-(5,6-Dimethoxypyridin-2-yl)-4-(2,4,6- trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.81

100 2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6- trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.61

101 2-(3,4-Dimethylphenyl)-4-(2,4,6- trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.46

102 4-(2,6-Difluoro-4-methoxybenzyl)-2-(3,4- dimethylphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 9.11

103 2-(3,5-Dimethylphenyl)-4-(2,4,6- trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.37

104 4-(2,4-Difluoro-6-methoxybenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.15

105 2-(3,4-Dimethoxyphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.71

106 4-(2-Chloro-6-fluoro-4-methylbenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide9.13

107 4-(2-Chloro-4,6-difluorobenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.98

108 2-(3,4-Dimethoxyphenyl)-4-(2,6-difluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 9.33

109 4-(2,6-Difluoro-4-methoxybenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.49

110 4-(2-Chloro-4,6-difluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.57

111 4-(2,6-Difluoro-4-methoxybenzyl)-2-[3-(methylsulfonyl)phenyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.65

112 2-[3-(Methylsulfonyl)phenyl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.57

113 4-(2-Chloro-6-fluoro-4-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide10.04

114 2-(4-Hydroxy-3,5-dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.89

115 2-(4-methoxy-3,5-dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 9.45

116 4-(2,6-Difluoro-4-hydroxybenzyl)-2-(3,4- dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.94

117 4-(2-Chloro-6-fluorobenzyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide6.43

118 4-(2-Chloro-6-fluorobenzyl)-2-[(3-methyloxetan-3-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 6.43

119 4-(2,6-Difluorobenzyl)-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.18

120 4-(2,6-Difluorobenzyl)-2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide6.75

121 4-(2,6-Difluorobenzyl)-2-[(3,4-dimethoxypyridin-2-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 7.06

122 4-(2-Chloro-6-fluorobenzyl)-2-(6- methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.78

123 4-(2-Chloro-6-fluorobenzyl)-5-fluoro-2-(6-methoxypyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.36

124 2-(1,3-Benzothiazol-6-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.3

125 4-(2,6-Difluorobenzyl)-2-[(1-methyl-1H-indazol-3-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.42

126 4-(2,6-Difluorobenzyl)-2-[(2-oxo-1,2-dihydroquinolin-4-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 7.45

127 4-(2-Chloro-6-fluorobenzyl)-2-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-2H- 1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide 7.23

128 4-(2-Chloro-6-fluorobenzyl)-2-(pyridin-2-ylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)- one 1,1-dioxide 7.1

129 4-(2-Chloro-6-fluorobenzyl)-2-[(5-methyl-1,2-oxazol-3-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide6.94

130 5-Fluoro-2-(6-methoxypyridin-3-yl)-4-(2-methylbenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.06

131 4-(2,6-Difluorobenzyl)-2-[(1-methyl-1H-imidazol-2-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide6.53

132 4-(2-Chloro-6-fluorobenzyl)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 6.52

133 4-(2,6-Difluorobenzyl)-2-(1-ethylpiperidin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 6.18

134 4-(4-Chloro-2-fluorobenzyl)-2-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-2H- 1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide 7.4

135 4-(2-Chloro-6-fluoro-4-methylbenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 7.86

136 4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide7.97

137 4-(2-Chloro-6-fluorobenzyl)-2-(2- methoxypyrimidin-5-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.42

138 4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxypyridin-2-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.84

139 4-(2-Chloro-4,6-difluorobenzyl)-2-(6- methoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.86

140 4-(2,6-Difluoro-4-methoxybenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.48

141 4-(2-Chloro-4,6-difluorobenzyl)-2-(2- methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.16

142 4-(2-Chloro-6-fluorobenzyl)-2-(6- methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.53

143 4-(2-Chloro-6-fluorobenzyl)-2-(2- methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 7.8

144 2-(6-Methoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.3

145 2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.33

146 4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-Dimethoxypyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide9.44

147 2-(5,6-Dimethoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.8

148 2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.86

149 4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide9.86

150 4-(2-Chloro-6-fluorobenzyl)-2-(1-ethyl-1H-pyrazol-4-yl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.76

151 4-(2-Chloro-6-fluorobenzyl)-2-[5-(methylsulfanyl)pyridin-3-yl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 8.7

152 2-[5-(Methylsulfanyl)pyridin-3-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.23

153 4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide9.65

154 4-(2-Chloro-6-fluoro-4-methoxybenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.52

155 4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.76

156 4-(2,4,6-Trifluorobenzyl)-2-[(2-oxo-1,2-dihydroquinolin-4-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 7.95

157 4-(2-Chloro-4,6-difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide9.24

158 2-[6-(Dimethylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.47

159 2-[2-(Dimethylamino)pyridin-4-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.51

160 2-[6-(Methylsulfanyl)pyridin-3-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 7.76

161 4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.9

162 2-(2,6-Dimethoxypyridin-4-yl)-4-[(5-fluoro-3-methylpyridin-2-yl)methyl]-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 7.73

163 4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6- dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.86

164 4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6- dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 9.18

165 4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6- dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 9.17

166 4-(2-Chloro-6-fluorobenzyl)-2-(2,6- dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.57

167 4-(2,6-Difluorobenzyl)-2-(2,6- dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide 8.66

168 4-(2-Chloro-6-fluorobenzyl)-2-(5,6- dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.91

169 4-(2,-Difluorobenzyl)-2-(5,6- dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 9.07

170 2-(4,5-dimethoxypyrimidin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin- 3(4H)-one 1,1-dioxide 8.14

171 4-(2,6-difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one1,1-dioxide 8.75

172 2-[6-methoxy-5-(methylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.11

173 4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6- dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.62

174 4-(2,6-difluoro-4-methoxybenzyl)-2-(4,6- dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.14

175 4-(2,6-difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.87

176 2-(5-methoxy-6-methylpyridin-3-yl)-4- (2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.19

177 4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.66

178 4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.36

179 4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-2-yl]- 2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide 8.43

180 4-(2-chloro-4,6-difluorobenzyl)-2-(2,6- dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.69

181 4-(2,6-difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]- 2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide 8.79

182 2-(1,3-benzothiazol-6-yl)-4-(2,6-difluoro- 4-methoxybenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.35

183 4-(2,6-difluoro-4-methoxybenzyl)-2-(4,6-dimethoxypyridin-2-yl)-2H-1,2,4- benzothiadiazin-3(4H)-one 1,1-dioxide8.56

184 4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methyl-6-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.07

185 4-(2-chloro-4,6-difluorobenzyl)-2-(5,6- dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.38

186 4-(2,6-difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide 8.90

Synthesis of Examples General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on Bruker or JEOLinstruments. Chemical shift values are expressed in parts per million(ppm), i.e. (□)-values. The following abbreviations are used for themultiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quin=quintet, h=heptet, dd=doublet of doublets,dt=double of triplets, m=multiplet. Coupling constants are listed as Jvalues, measured in Hz. ¹H NMR and mass spectroscopy results werecorrected to account for background peaks.

Chromatography refers to column chromatography performed using 60-120mesh silica gel and executed under nitrogen pressure (flashchromatography) conditions. TLC for monitoring reactions refers to TLCrun using the specified mobile phase and the Silica gel F254 as astationary phase from Merck. Microwave-mediated reactions were performedin Biotage Initiator or CEM Discover microwave reactors.

Mass spectroscopy was carried out on Shimadzu LC-2010 EV, WatersZQ-2000, UPLC-Mass SQD-3100 or Applied Biosystem API-2000 spectrometersusing electrospray conditions as specified for each compound in thedetailed experimental section.

Preparative HPLC was typically carried out under the followingconditions. Method A (Gilson HPLC): Column: PrepHT Extend C-18, 21.2×100mm, 5 micron; Mobile phase: Gradients of water and MeCN (each containing0.1% Formic Acid); Gradient: 5% MeCN to 95% MeCN in water over 16.30minutes at 28 mL/min. Method B (Waters HPLC): Column: XSelect CSH PrepC-18, 19×50 mm, 5 micron; Mobile phase: Gradients of water and MeCN(each containing 0.1% Formic Acid); Gradient: 5% MeCN to 95% MeCN inwater over 16.30 minutes at 28 mL/min. Method C (Gilson HPLC): Column:Waters XBridge Prep C-18, 19×150 mm, 5 micron; Mobile phase: Gradientsof water and MeOH (each containing 0.1% NH₃); Gradient: 10% MeOH to 95%MeOH in water over 14.50 minutes at 18 mL/min.

LCMS experiments were typically carried out using electrosprayconditions as specified for each compound under the followingconditions. Instruments: Waters Alliance 2795, Waters 2996 PDA detector,Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm orPhenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time(min)/solvent D in C (%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95,3.55/2, 4.00/2 or Method B: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2,10.00/2; Solvents: solvent C=2.5 L H₂O+2.5 mL ammonia solution; solventD=2.5 L MeCN+135 mL H₂O+2.5 mL ammonia solution); Injection volume 3 uL;UV detection 230 to 400 nM; column temperature 45° C.; Flow rate 1.5mL/min. LCMS data in the experimental section are given in the format:Mass ion, retention time, approximate purity.

ABBREVIATIONS

-   Ar=argon-   BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthalene-   Boc₂O=Di-tert-butyl dicarbonate-   d=day(s)-   DCM=dichloromethane-   DMAC=N,N-dimethylacetamide-   DMF=dimethylformamide-   DMSO=dimethylsulfoxide-   ESI=electrospray ionisation-   EtOAc=ethyl acetate-   h=hour(s)-   HPβCD=(2-hydroxypropyl)-β-cyclodextrin-   HPLC=high performance liquid chromatography-   L=Liter-   LC=liquid chromatography-   MeCN=acetonitrile-   min=minute(s)-   MS=mass spectrometry-   NMR=nuclear magnetic resonance-   rt=room temperature-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography

Prefixes n-, s-, i-, t- and tert-have their usual meanings: normal,secondary, iso, and tertiary.

SYNTHESIS OF INTERMEDIATES Route 1 Typical procedure for the preparationof cyclised intermediates, as exemplified by the preparation of2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntA1)

Step 1: Preparation of N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide

A mixture of 2-nitrobenzenesulfonyl chloride (3.0 g, 13.5 mmol) and3,4-dimethoxyaniline (2.1 g, 14.9 mmol) in 1,4-dioxane (30 mL) in asealed reaction tube was heated at 80° C. for 24 h with TLC monitoring(hexane:EtOAc, 1:1). The reaction mixture was diluted with H₂O (30 mL),extracted with EtOAc (3×100 mL) and the combined organic phases driedover Na₂SO₄, filtered and concentrated in vacuo. Purification bygradient flash chromatography, eluting with 20-25% EtOAc in hexaneyielded the title compound (2.5 g, 7.39 mmol).

Mass spectroscopy: (ESI+ve) 339 [M+H]⁺

Step 2: Preparation of 2-amino-N-(3,4-dimethoxyphenyl)benzenesulfonamide

A mixture of N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide (2.5 g,7.39 mmol) and SnCl₂ (8.34 g, 36.9 mmol) in ethanol was heated at 100°C. for 5 h in a sealed tube with TLC monitoring (hexane:EtOAc, 1:1).After concentration in vacuo H₂O (30 mL) was added and the mixture wasextracted with EtOAc (3×100 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo. Purification bygradient flash chromatography, eluting with 20-25% EtOAc in hexaneyielded the title compound (2.0 g, 6.49 mmol).

Mass spectroscopy: (ESI+ve) 309.1 [M+H]⁺

Step 3: Preparation of2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide

A mixture of 2-amino-N-(3,4-dimethoxyphenyl)benzenesulfonamide (0.8 g,2.6 mmol) and triphosgene (0.99 g, 3.4 mmol) in anhydrous 1,4-dioxanewas heated in a sealed tube at 100° C. overnight with TLC monitoring(hexane:EtOAc, 1:1). After concentration in vacuo H₂O (30 mL) was addedand the mixture was extracted with EtOAc (3×100 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by gradient flash chromatography, eluting with 20-25% EtOAcin hexane yielded the title compound (0.4 g, 1.20 mmol).

Mass spectroscopy: (ESI+ve) 335.1 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 3.73 (s, 3H), 3.82 (s, 3H), 6.89-7.02 (m,2H), 7.08 (d, J=8.5, 1H), 7.30-7.41 (m, 2H), 7.71-7.81 (m, 1H), 7.89 (d,J=7.3, 1H), 11.53 (s, 1H)

2-(3,4,5-Trimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA2, Y48A)

The title compound (2.0 g, 5.49 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (7.0 g, 31.6 mmol) and3,4,5-trimethoxyaniline (6.3 g, 31.6 mmol) using the methods of (IntA1).

Mass spectroscopy: (ESI+ve) 365.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 3.73 (s, 3H), 3.77 (s, 6H), 6.73 (s, 2H),7.27-7.43 (m, 2H), 7.77 (t, J=7.8, 1H), 7.90 (d, J=7.9, 1H), 11.58 (s,1H)

2-(6-Methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntA3)

The title compound (2.18 g, 7.53 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (6.15 g, 27.7 mmol) and6-methylpyridin-3-amine (3.0 g, 27.7 mmol) using the methods of (IntA1).

Mass spectroscopy: (ESI+ve) 290.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 2.56 (s, 3H), 7.26-7.43 (m, 2H), 7.46 (d,J=7.9, 1H), 7.72-7.86 (m, 2H), 7.93 (d, J=7.9, 1H), 8.47 (d, J=1.2, 1H),11.72 (s, 1H)

2-(2-Methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntA4)

The title compound (2.2 g, 7.21 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (16.0 g, 72.5 mmol),2-methoxy-4-aminopyridine (10.0 g, 80.6 mmol) and triethylamine (8.95 g,88.6 mmol) using the methods of (IntA1).

Mass spectroscopy: (ESI+ve) 305.9 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 3.92 (s, 3H), 6.94 (d, J=1.5, 1H), 7.11 (dd,J=5.3, 1.7, 1H), 7.30-7.45 (m, 2H), 7.72-7.85 (m, 1H), 7.93 (d, J=7.6,1H), 8.34 (d, J=5.5, 1H), 11.75 (s, 1H)

2-(6-Methoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntA5)

The title compound (0.6 g, 1.97 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (5.5 g, 24.8 mmol),2-amino-6-methoxypyridine (3.08 g, 24.8 mmol) and triethylamine (2.75 g,27.2 mmol) using the methods of (IntA1).

Mass spectroscopy: (ESI+ve) 305.9 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 3.83 (s, 3H), 7.01 (d, J=8.2, 1H), 7.14 (d,J=7.3, 1H), 7.33-7.43 (m, 2H), 7.78 (t, J=7.9, 1H), 7.86-7.96 (m, 2H),11.67 (s, 1H)

2-(4-Methoxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA6)

The title compound (1.3 g, 5.42 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (2.93 g, 13.2 mmol) and4-methoxy-3,5-dimethylaniline (2.0 g, 13.20 mmol) using the methods of(IntA1).

Mass spectroscopy: (ESI+ve) 332.6 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 2.26 (s, 6H), 3.72 (s, 3H), 7.09 (s, 2H),7.31-7.40 (m, 2H), 7.77 (t, J=7.8, 1H), 7.89 (d, J=7.9, 1H), 11.59 (s,1H) 2-(1,3-Benzothiazol-6-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA7)

The title compound (0.80 g, 2.41 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (5.0 g, 22.6 mmol) and6-aminobenzothiazole (3.39 g, 22.6 mmol) using the methods of (IntA1).

Mass spectroscopy: (ESI+ve) 331.6 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 7.30-7.45 (m, 2H), 7.58 (d, J=8.5, 1H), 7.80(t, J=7.6, 1H), 7.94 (d, J=7.9, 1H), 8.22 (d, J=8.5, 1H), 8.36 (s, 1H),9.56 (s, 1H), 11.70 (br s, 1H)

2-(1-Ethyl-1H-pyrazol-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA8)

The title compound (0.80 g, 2.74 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (2.65 g, 11.9 mmol),1-ethyl-1H-pyrazol-4-amine hydrochloride (1.8 g, 12.0 mmol) andtriethylamine (3.0 g, 2.99 mmol) using the methods of (IntA1).

Mass spectroscopy: (ESI+ve) 292.5 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 1.41 (t, J=7.2, 3H), 4.19 (q, J=7.1, 2H),7.25-7.42 (m, 2H), 7.50-7.60 (m, 1H), 7.71-7.81 (m, 1H), 7.87-7.96 (m,1H), 8.09 (s, 1H), 11.60 (s, 1H)

2-[5-(Methylsulfanyl)pyridin-3-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA9)

The title compound (0.40 g, 1.24 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (0.78 g, 3.57 mmol) and5-(methylsulfanyl)pyridin-3-amine (0.5 g, 3.57 mmol) using the methodsof (IntA1).

Mass spectroscopy: (ESI+ve) 322.7 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 2.57 (s, 3H), 7.25-7.48 (m, 2H), 7.72-7.89(m, 2H), 7.94 (d, J=7.3, 1H), 8.39 (d, J=1.8, 1H), 8.62 (d, J=2.1, 1H),11.75 (s, 1H)

2-[6-(Methylsulfanyl)pyridin-3-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA10)

The title compound (2.0 g, 6.22 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (4.02 g, 19.6 mmol) and6-(methylsulfanyl)pyridin-3-amine (2.5 g, 17.9 mmol) using the methodsof (IntA1).

Mass spectroscopy: (ESI+ve) 322.7 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 2.57 (s, 3H), 7.33-7.45 (m, 2H), 7.50 (d,J=8.5, 1H), 7.69-7.84 (m, 2H), 7.94 (d, J=7.3, 1H), 8.45 (d, J=2.4, 1H),11.73 (s, 1H)

2-(3,5-Dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntA11)

The title compound (0.2 g, 0.60 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (1.0 g, 4.51 mmol) and3,5-dimethoxyaniline (0.7 g, 4.96 mmol) using the methods of (IntA1).

Mass spectroscopy: (ESI+ve) 335.1 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 3.77 (s, 6H), 6.56 (d, J=2.3, 2H), 6.68 (t,J=2.3, 1H), 7.29-7.42 (m, 2H), 7.70-7.82 (m, 1H), 7.89 (d, J=7.5, 1H),11.57 (br s, 1H)

2-[3-(Methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA12)

The title compound (2.0 g, 6.24 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride 5.0 g, 22.6 mmol) and3-(methylthio)aniline (3.45 g, 24.8 mmol) using the methods of (IntA1).

LCMS (Method B): m/z 321.2 (M+H)+ (ES+), 319.3 (M−H)− (ES−), at 2.65min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.51 (s, 3H), 7.21 (d, J=7.6, 1H), 7.27 (s,1H), 7.32-7.52 (m, 4H), 7.72-7.82 (m, 1H), 7.88-7.95 (m, 1H), 11.63 (s,1H)

2-[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA13)

The title compound (0.30 g, 0.98 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (0.5 g, 2.25 mmol) and1-(3-methyl-1H-pyrazol-5-yl)methanamine (0.32 g, 2.48 mmol) using themethods of (IntA1).

Mass spectroscopy: (ESI+ve) 307 [M+H]⁺.

2-{3-[(Trifluoromethyl)sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA14)

Step 1: Preparation of2-nitro-N-{3-[(trifluoromethyl)sulfanyl]phenyl}benzenesulfonamide

The title compound (1.26 g, 3.3 mmol) was prepared from2-nitrobenzenesulfonyl chloride (1.1 g, 5.0 mmol) and3-[(trifluoromethyl)sulfanyl]aniline (1.06 g, 5.5 mmol) using themethods of (IntA1), step 1.

LCMS (Method A): m/z 377 (M−H)− (ES−), at 1.21 min, 100%

Step 2: Preparation of2-amino-N-{3-[(trifluoromethyl)sulfanyl]phenyl}benzenesulfonamide

A solution of2-nitro-N-{3-[(trifluoromethyl)sulfanyl]phenyl}benzenesulfonamide (605mg, 1.6 mmol) in ethanol/H₂O (4:1, 50 mL total reaction volume) wasadded to a suspension of 10% palladium on charcoal (50 mg) inethanol/H₂O (4:1) and the mixture stirred at rt under an atmosphere ofH₂ for approximately 2 d. After this time further 10% palladium oncharcoal (75 mg) was added and the reaction mixture stirred under anatmosphere of H₂ at rt for 3 h. Filtration and concentration in vacuoyielded the title compound (455 mg, 1.31 mmol).

LCMS (Method A): m/z 347 (M−H)− (ES−), at 1.37 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 6.02 (br s, 2H), 6.47-6.62 (m, 1H), 6.76 (d,J=7.5, 1H), 7.16-7.27 (m, 2H), 7.28-7.34 (m, 1H), 7.34-7.44 (m, 2H),7.51 (dd, J=8.0, 1.3, 1H)

Step 3: Preparation of2-{3-[(trifluoromethyl)sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide

A mixture of2-amino-N-{3-[(trifluoromethyl)sulfanyl]phenyl}benzenesulfonamide (52mg, 0.15 mmol), 1,1′-carbonyldiimidazole (97 mg, 0.60 mmol) andtriethylamine (41 μL, 0.30 mmol) in DMF (0.75 mL) was heated in a sealedtube for 5 h at 100° C. After concentration in vacuo, DCM and 1M aqueousHCl were added, the phases were separated, the organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo.Purification by flash chromatography, eluting with 3% MeOH in DCMyielded the title compound (45 mg, 0.21 mmol).

LCMS (Method A): m/z 373 (M−H)− (ES−), at 1.50 min, 100%

¹H NMR: (400 MHz, DMSO) δ 7.33-7.43 (m, 2H), 7.69-7.84 (m, 4H),7.88-7.97 (m, 2H), 11.70 (s, 1H)

2-(6-Methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntA15)

Step 1: Preparation ofN-(6-Methoxypyridin-3-yl)-2-nitrobenzenesulfonamide

The title compound (1.05 g, 3.4 mmol) was prepared from2-nitrobenzenesulfonyl chloride (1.1 g, 5.0 mmol) and5-amino-2-methoxypyridine (683 mg, 5.5 mmol) using the methods of(IntA1), step 1.

LCMS (Method A): m/z 310 (M+H)+ (ES+), at 0.41 min, 95%

Step 2: Preparation of2-amino-N-(6-methoxypyridin-3-yl)benzenesulfonamide

The title compound (419 mg 1.50 mmol) was prepared fromN-(6-Methoxypyridin-3-yl)-2-nitrobenzenesulfonamide (500 mg, 1.62 mmol)and 10% palladium on charcoal (50 mg) using the methods of (IntA14),step 2.

LCMS (Method A): m/z 280 (M+H)+ (ES+), at 0.88 min, 90%

Step 3: Preparation of2-(6-Methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide

The title compound (143 mg, 0.47 mmol) was prepared from2-amino-N-(6-methoxypyridin-3-yl)benzenesulfonamide (209 mg, 0.75 mmol),1,1′-carbonyldiimidazole (486 mg, 3.0 mmol) and triethylamine (0.28 mL,1.5 mmol) in DMF (3.75 mL) using the methods of (IntA14), step 3.

LCMS (Method A): m/z 306 (M+H)+ (ES+), at 1.05 min, 100%

¹H NMR: (400 MHz, DMSO) δ 3.93 (s, 3H), 7.00 (d, J=8.8, 1H), 7.30-7.44(m, 2H), 7.73-7.84 (m, 2H), 7.93 (d, J=7.8, 1H), 8.21 (d, J=2.5, 1H),11.66 (s, 1H)

2-Amino-4-fluoro-N-[3-(methylsulfanyl)phenyl]benzenesulfonamide (IntA16)

Step 1: Preparation of4-fluoro-N-[3-(methylsulfanyl)phenyl]-2-nitrobenzenesulfonamide

A solution of 3-(methylsulfanyl)aniline (658 mg, 4.73 mmol) and pyridine(995 uL, 18.9 mmol) was cooled to 0° C. under N₂ before the dropwiseaddition of bis(trimethylsilyl)trifluorocetamide (1.76 mL, 9.45 mmol)over 5 min. After stirring for 5 min at 0° C., a solution of4-fluoro-2-nitrobenzenesulfonyl chloride (1.19 g, 4.97 mmol) in1,4-dioxane (7 mL) was added dropwise over 15 min. The mixture wasstirred at rt for 1 h, then at 100° C. for 30 min. After cooling to rt,the mixture was concentrated in vacuo and partitioned between DCM and 1Maqueous HCl (25 mL each). The phases were separated and the aqueouslayer extracted with DCM (2×25 mL). The combined organic layers wereconcentrated in vacuo and purified by gradient flash chromatography,eluting with 5-50% EtOAc in heptane to yield the title compound (865 mg,2.53 mmol).

LCMS (Method B): m/z 341.2 (M−H)− (ES−), at 1.90 min, 90%

¹H NMR: (400 MHz, DMSO) δ 2.39 (s, 3H), 6.79-6.92 (m, 1H), 6.93-7.04 (m,2H), 7.15-7.29 (m, 1H), 7.74 (td, J=8.4, 2.8, 1H), 8.04 (dd, J=8.8, 5.3,1H), 8.13 (dd, J=8.2, 2.6, 1H), 10.84 (s, 1H)

Step 2: Preparation of2-amino-4-fluoro-N-[3-(methylsulfanyl)phenyl]benzenesulfonamide

The title compound (780 mg, 2.50 mmol) was prepared from4-fluoro-N-[3-(methylsulfanyl)phenyl]-2-nitrobenzenesulfonamide (865 mg,2.53 mmol) and SnCl₂ (1.44 g, 7.59 mmol) using the methods of (IntA1),Step 2.

LCMS (Method B): m/z 311.1 (M−H)− (ES−), at 2.17 min, 100%

¹H NMR: (400 MHz, DMSO) δ 2.39 (s, 3H), 6.27 (s, 2H), 6.41 (td, J=8.5,2.5, 1H), 6.52 (dd, J=11.5, 2.5, 1H), 6.81 (dd, J=8.0, 1.0, 1H), 6.89(dd, J=3.6, 1.6, 2H), 7.10-7.22 (m, 1H), 7.56 (dd, J=9.0, 6.5, 1H),10.31 (s, 1H)

2-[6-(Dimethylamino)pyridin-2-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA17)

Step 1: Preparation ofN-[6-(dimethylamino)pyridin-2-yl]-2-nitrobenzenesulfonamide

A solution of N,N-dimethylpyridine-2,6-diamine (1.0 g, 7.2 mmol),2-nitrobenzenesulfonyl chloride (1.45 g, 6.4 mmol) and pyridine (2.27 g,28.8 mmol) in diethyl ether (25 mL) was heated at 30° C. forapproximately 12 h with TLC monitoring (hexane:EtOAc, 1:1). Afterconcentration in vacuo purification by gradient flash chromatography,eluting with 0-25% EtOAc in hexane yielded the target compound (1.0 g,3.10 mmol).

TLC: Rf=0.70 (hexane:EtOAc, 1:1)

Mass spectroscopy: (ESI+ve) 322.9 [M+H]⁺

Step 2: Preparation of2-amino-N-[6-(dimethylamino)pyridin-2-yl]benzenesulfonamide

In a sealed tube, a mixture ofN-[6-(dimethylamino)pyridin-2-yl]-2-nitrobenzenesulfonamide (1.0 g, 3.10mmol) and Fe powder (0.85 g, 11.5 mmol) in acetic acid (10 mL) washeated at 60° C. for approximately 15 min with TLC monitoring(hexane:EtOAc, 1:1). The reaction mixture was poured into saturatedaqueous NaHCO₃ solution (100 mL) and extracted with EtOAc (3×50 mL), thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. Purification by gradient flash chromatography, eluting with 0-45%EtOAc in hexane yielded the title compound (0.7 g, 2.39 mmol).

TLC: Rf=0.65 (hexane: EtOAc, 1:1)

Mass spectroscopy: (ESI+ve) 293.2 [M+H]⁺

Step 3: Synthesis of2-[6-(dimethylamino)pyridin-2-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide

The title compound (0.20 g, 0.63 mmol) was prepared from2-amino-N-[6-(dimethylamino)pyridin-2-yl]benzenesulfonamide (0.7 g, 2.39mmol) and triphosgene (2.5 g, 8.3 mmol) in 1,4-dioxane (25 mL) using themethods of (IntA1).

TLC: Rf=0.70 (hexane:EtOAc, 1:1)

Mass spectroscopy: (ESI+ve) 318.9 [M+H]⁺

2-[2-(Dimethylamino)pyridin-4-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA18)

The title compound (0.12 g, 0.38 mmol) was prepared in three steps fromN²,N²-dimethylpyridine-2,4-diamine (2.29 g, 16.6 mmol),2-nitrobenzenesulfonyl chloride (3.3 g, 15 mmol) and pyridine (13.1 g,16.6 mmol) using the methods of (IntA17).

TLC: Rf=0.70 (hexane:EtOAc, 1:1)

Mass spectroscopy: (ESI+ve) 318.9 [M+H]⁺.

2-(5,6-Dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA19)

Step 1: Preparation ofN-(5,6-Dimethoxypyridin-3-yl)-2-nitrobenzenesulfonamide

The title compound (1.56 g, 4.60 mmol) was prepared from2-nitrobenzenesulfonyl chloride (2.66 g, 12.0 mmol),5,6-dimethoxy-3-pyridinamine (2.04 g, 13.2 mmol) and pyridine (2.9 mL,36.0 mmol) using the methods of (IntA1), step 1.

LCMS (Method A): m/z 340 (M+H)+ (ES+), at 0.12 and 0.72 min, 90%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.79 (s, 3H), 7.03 (d, J=2.3,1H), 7.39 (d, J=2.0, 1H), 7.81-7.89 (m, 2H), 7.97 (ddd, J=7.3, 5.4, 1.9,2H), 10.52 (s, 1H)

Step 2: Preparation of2-amino-N-(5,6-dimethoxypyridin-3-yl)benzenesulfonamide

The title compound (486 mg) was prepared fromN-(5,6-dimethoxypyridin-3-yl)-2-nitrobenzenesulfonamide (509 mg, 1.5mmol), Fe powder (559 mg, 15.0 mmol) and acetic acid (10 mL) using themethods of (IntA17), Step 2.

LCMS (Method B): m/z 310 (M+H)+ (ES+), at 0.11 and 1.02 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.66 (s, 3H), 3.76 (s, 3H), 6.00 (br. s, 2H),6.54 (t, J=7.2, 1H), 6.77 (d, J=8.3, 1H), 6.91 (d, J=2.3, 1H), 7.17-7.28(m, 1H), 7.33 (d, J=2.3, 1H), 7.40 (dd, J=8.0, 1.3, 1H), 10.00 (br. s,1H)

Step 3: 2-(5,6-Dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide

The title compound (257 mg, 0.77 mmol) was prepared from2-amino-N-(5,6-dimethoxypyridin-3-yl)benzenesulfonamide (486 mg, 1.57mmol), 1,1′-carbonyldiimidazole (1.02 g, 6.29 mmol) and triethylamine(0.44 mL, 3.14 mmol) in DMF (3 mL) using the methods of (IntA14), step3.

LCMS (Method B): m/z 336 (M+H)+ (ES+), at 2.65 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.79 (s, 3H), 3.94 (s, 3H), 7.18-7.52 (m,3H), 7.63-7.85 (m, 2H), 7.93 (dd, J=8.2, 1.1, 1H), 11.65 (br. s, 1H)

2-(5,6-Dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA20)

The title compound (0.30 g, 0.89 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (1.05 g, 4.72 mmol),5,6-dimethoxypyridin-2-amine (0.80 g, 5.19 mmol) and pyridine (1.15 mL,14.2 mmol) in 1,4-dioxane (19 mL) using the methods of (IntA19).

LCMS (Method A): m/z 334 (M−H)− (ES−), 336 (M+H)+ (ES+), at 0.17 and1.11 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.82 (s, 3H), 3.86 (s, 3H), 7.10 (d, J=8.0,1H), 7.32-7.41 (m, 2H), 7.46 (d, J=8.0, 1H), 7.72-7.82 (m, 1H), 7.89(dd, J=8.0, 1.3, 1H), 11.59 (s, 1H)

2-(2,6-Dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA21)

The title compound (0.40 g, 1.19 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (2.66 g, 12.0 mmol),2,6-dimethoxypyridin-4-amine (2.04 g, 13.2 mmol) and pyridine (2.9 mL,36.0 mmol) in 1,4-dioxane (48 mL) using the methods of (IntA19).

LCMS (Method B): m/z 336 (M+H)+ (ES+), at 2.12 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.91 (s, 6H), 6.47 (s, 2H), 7.36 (t, J=8.2,2H), 7.78 (dt, J=8.2, 0.9, 1H), 7.92 (d, J=7.8, 1H), 11.66 (br. s, 1H)

(2-Chloro-4,6-difluorophenyl)methanol (IntA22)

Step 1: Preparation of (4-chloro-2,6-difluorophenyl)trimethylsilane

A solution of 2.5M n-BuLi in hexanes (60 ml, 0.15 mol) was addeddropwise to a solution of 1-chloro-3,5-difluorobenzene (19.2 g, 0.13mol) in THF (200 mL) cooled to −70° C. under Ar. After the addition wascomplete, the mixture was stirred for 1 h before a solution ofchlorotrimethylsilane (21.7 g, 0.2 mol) in THF (25 mL) was addeddropwise. The reaction was allowed to warm to rt with stirring overnightbefore cooling and quenching with H₂O. The phases were separated andpentane (200 mL) was added; after washing with H₂O the solution wasdried over MgSO₄ and carefully concentrated in vacuo to yield the titlecompound as a solution in THF (46 g) which was in the next step withoutfurther purification.

Step 2: Preparation of6-chloro-2,4-difluoro-3-(trimethylsilyl)benzaldehyde

A solution of 2.5M n-BuLi in hexanes (60 ml, 0.15 mol) was addeddrop-wise to a solution of (4-chloro-2,6-difluorophenyl)trimethylsilane(assumed 0.13 mol) in THF (180 mL) cooled to −70° C. under Ar. After theaddition was complete, the mixture was stirred for 1 h before a solutionof N-formylmorpholine (20 mL, 0.2 mol) in THF (25 mL) was addeddropwise. The reaction was allowed to warm to rt with stirring and thencooled to 0° C. and quenched with H₂O. Ether was added, the phases wereseparated, the aqueous phase was re-extracted with ether and thecombined organics washed with brine, dried over MgSO₄ and concentratedin vacuo to give the title compound (35 g) as an orange oil which wasused without further purification.

Step 3: Preparation of 2-chloro-4,6-difluorobenzaldehyde

CsF (approximately 0.2 g) was added to a mixture of crude6-chloro-2,4-difluoro-3-(trimethylsilyl)benzaldehyde (10.5 g,approximately 42 mmol) in dimethylformamide (15 mL)/H₂O (2 mL). Afterstirring for 10 min the reaction was diluted with heptane and H₂O. Thephases were separated and the aqueous extracted with further heptane.The combined organic layers were washed with H₂O, dried over MgSO₄ andconcentrated in vacuo to a yellow oil. Purification by columnchromatography (1:4 EtOAc:heptane) followed by trituration with pentanegave the title compound as a white solid (3.0 g, 17.0 mmol).

TLC: Rf=0.54 (8:7 heptane:EtOAc)

Step 4: Preparation of (2-chloro-4,6-difluorophenyl)methanol

Sodium borohydride (1.42 g, 37.5 mmol) was added in portions to anice-cooled solution of 2-chloro-4,6-difluorobenzaldehyde (6.70 g, 38.0mmol) in methanol (56 ml); once addition was complete the reaction waswarmed to rt over 1 h and then concentrated in vacuo. The residue waspartitioned between ether and saturated sodium bicarbonate solution, thephases were separated and the aqueous phase extracted with more ether.The combined organic phases were washed with H₂O, dried with MgSO₄ andconcentrated in vacuo to yield the crude product as an oil which wasdiluted with pentane (20 mL) and allowed to stand in a freezerovernight. The liquors were decanted from the resultant white crystalswhich were then dried in vacuo to yield the title compound (5.60 g, 31.4mmol).

TLC: Rf=0.43 (8:7 heptane:EtOAc)

¹H NMR: (400 MHz, DMSO) δ: 4.54 (dd, J=5.5, 2.3, 2H), 5.26 (t, J=5.5,1H), 7.17-7.46 (m, 2H)

(2,4-Difluoro-6-methoxyphenyl)methanol (IntA23)

Step 1: Preparation of methyl 2,4-difluoro-6-methoxybenzoate

Methyl iodide (1.97 mL, 31.6 mmol) was added to a suspension of2,4-difluoro-6-hydroxybenzoic acid (2.50 g, 14.4 mmol) and K₂CO₃ (5.96g, 43.1 mmol) in acetone (50 mL) and the mixture heated at reflux for 12h. After concentration in vacuo the material was suspended in DCM (50mL) and filtered, rinsing the residue with DCM (2×50 mL). The combinedfiltrates were concentrated in vacuo and purified by gradient flashchromatography eluting with 5-40% EtOAc in iso-hexane to yield the titlecompound (1.15 g, 5.71 mmol).

¹H NMR: (400 MHz, DMSO) δ: 3.83 (s, 3H), 3.84 (s, 3H), 6.92-7.03 (m, 2H)

Step 2: Preparation of (2,4-difluoro-6-methoxyphenyl)methanol

A solution of LiBH₄ (2M in THF, 6.28 mL, 12.6 mmol) was added to asolution of methyl 2,4-difluoro-6-methoxybenzoate (1.15 g, 5.71 mmol) inTHF (30 mL). The solution was stirred at rt for 23 h, then at 60° C. for4.5 h, and reflux for 18.5 h. After cooling to rt, H₂O (20 mL) was addeddropwise and the mixture stirred for 5 min before being partiallyconcentrated in vacuo. DCM (20 mL) was added, the phases were separated,and the aqueous phase was extracted with DCM (2×10 mL). The organiclayers were concentrated in vacuo to yield the title compound (978 mg,5.62 mmol).

LCMS (Method B): Molecular ions not observed, at 1.78 min, 85%

¹H NMR: (400 MHz, DMSO) δ: 3.83 (s, 3H), 4.41 (dd, J=5.4, 1.9, 2H), 4.85(t, J=5.5, 1H), 6.69-6.86 (m, 2H)

(2-Chloro-6-fluoro-4-methylphenyl)methanol (IntA24)

Step 1: Preparation of 2-chloro-6-fluoro-4-methylbenzaldehyde

Under Ar, a 2.5M solution of n-BuLi (6.0 mL, 15.0 mmol) was added slowlyto a solution of 3-chloro-5-fluorotoluene (2.0, 13.8 mmol) in THF (20mL) cooled in a dry ice/acetone bath at approximately −70° C. After theaddition was complete, the reaction was stirred for 1 h at approximately−70° C. and a solution of N-formylmorpholine (2.3 g, 2.0 mmol) in THF(10 mL) was added dropwise. After stirring for 10 min, the reaction wasallowed to warm to rt with stirring over 1 h, then cooled to −30° C. andquenched by the addition of H₂O then 1M citric acid. The mixture wasallowed to warm to rt with stirring and the phases were separated. Theaqueous phase was extracted with EtOAc and the combined organic phaseswere washed with H₂O, dried with MgSO₄ and concentrated to yield thetitle compound as an oil which solidified on standing (2.2 g, 12.8mmol).

TLC: Rf=0.22 (4:1 heptane:EtOAc)

Step 2: Preparation of (2-chloro-6-fluoro-4-methylphenyl)methanol

Sodium borohydride (1.42 g, 37.5 mmol) was added in portions to anice-cooled solution of 2-chloro-6-fluoro-4-methylbenzaldehyde (6.25 g,38.2 mmol) in methanol (56 mL); once addition was complete the reactionwas allowed to warm rt with stirring over 1 h and then concentrated invacuo. The residue was partitioned between ether and saturated aqueoussodium bicarbonate solution. The layers were separated and the aqueousre-extracted with ether. The organic layers were combined, washed withH₂O, dried with MgSO₄ and concentrated in vacuo to yield the crudeproduct as an oil. This oil was diluted with pentane, cooled and stirredwhich resulted in a white solid. Filtration and drying in vacuo yieldedthe title compound (5.10 g, 29.2 mmol).

TLC: Rf=0.45 (8:7 heptane:EtOAc)

¹H NMR: (400 MHz, DMSO) δ: 2.36 (s, 3H), 4.58 (d, J=3.3, 2H), 5.20 (t,J=5.1, 1H), 7.10 (d, J=10.5, 1H), 7.21 (s, 1H)

2-Chloro-6-fluoro-4-methoxybenzyl alcohol (IntA25)

Step 1: Preparation of 3-chloro-5-fluoro-4-(hydroxymethyl)phenol

3-Chloro-5-fluorophenol (703 mg, 4.8 mmol) was added to a solution ofpotassium hydroxide (297 mg, 5.3 mmol) in H₂O (1.45 mL) and heated at60° C. Formaldehyde (37 wt % in H₂O, 0.74 mL, 9.12 mmol) in H₂O (1.45mL) was added dropwise and the reaction mixture left to stir at 40° C.overnight. The reaction mixture was cooled to rt and conc. HCl(approximately 6 mL) was added. The resultant precipitate was filtered,washed with H₂O and dried to yield the title compound as a cream solid(334 mg, 1.89 mmol).

LCMS (Method A): m/z 175, 177 (M−H)− (ES−), at 0.12 min, 95%

Step 2: Preparation of 2-chloro-6-fluoro-4-methoxybenzyl alcohol

Methyl iodide (0.13 mL, 2.08 mmol) was added dropwise to a solution of3-chloro-5-fluoro-4-(hydroxymethyl)phenol (334 mg, 1.89 mmol) andpotassium carbonate (287 mg, 2.08 mmol) in DMF (5 mL) and the reactionmixture stirred for 4 h at rt. The reaction mixture was partitionedbetween DCM and H₂O, the organic layer separated and the aqueous furtherextracted with DCM. The combined organic phases were concentrated invacuo to yield the title compound as a yellow oil (360 mg, 1.89 mmol).

LCMS (Method A): No ionisation seen, at 1.24 min, 95%

¹H NMR: (400 MHz, DMSO) δ 3.79 (s, 3H), 4.50 (dd, J=5.3, 2.0, 2H), 5.07(t, J=5.5, 1H), 6.86 (dd, J=11.5, 2.5, 1H), 6.90-6.95 (m, 1H)

(5-Fluoro-3-methylpyridin-2-yl)methanol (IntA26)

Sodium borohydride (125 mg, 3.3 mmol) was added to a solution of5-fluoro-3-methylpyridine-2-carbaldehyde (417 mg, 3.0 mmol) in EtOH (10mL) and stirred at rt for 3 h. The reaction was quenched by dropwiseaddition of saturated aqueous NH₄Cl solution (10 mL) and stirred for 15h. The reaction mixture was extracted twice with DCM and the combinedorganic phases were concentrated in vacuo. Purification by gradientcolumn chromatography, eluting with 10-60% EtOAc in iso-hexane to yieldthe title compound (218 mg, 51%).

LCMS (Method A): m/z 141.8 (M+H)+ (ES+), at 0.85 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.36 (s, 3H), 4.55 (d, J=5.5, 2H), 5.07 (t,J=5.5, 1H), 7.57 (dd, J=9.8, 2.5, 1H), 8.31 (d, J=2.5, 1H)

4-(2,6-Difluoro-4-(tert-butyldimethylsilyloxy)benzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA27)

tert-Butyl(chloro)dimethylsilane (6.42 g, 42.6 mmol) was added to asolution of 2,6-difluoro-4-hydroxybenzoic acid (3.09 g, 17.8 mmol) inTHF (50 mL), followed by the addition of N,N-diisopropylethylamine (9.19mL, 51.5 mmol) over 5 min. After stirring at rt for 10 min the solutionwas concentrated in vacuo. Purification by gradient columnchromatography, eluting with 10-50% solvent A in solvent B (A=DCM,B=DCM:MeOH:AcOH 95:5:1) yielded2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzoic acid (615 mg). Thismaterial was dissolved in THF (20 mL), borane-THF complex (1.0M in THF,6.4 mL, 6.4 mmol) was added and the solution stirred at rt for 4 h.Further borane-THF complex (1.0M in THF, 6.4 mL, 6.4 mmol) was added andthe solution stirred at rt for 18.5 h before concentration in vacuo.Purification by gradient column chromatography, eluting with 0-10% EtOAcin iso-hexane yielded 2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzylalcohol (470 mg). The title compound (533 mg, 0.90 mmol) wassubsequently prepared from2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzyl alcohol (356 mg, 1.30mmol) and (IntA1) (289 mg) using the methods of (77).

LCMS (Method B): m/z 591.2 (M+H)+ (ES+), at 6.35 min, 90%

TLC: Rf=0.86 (9:1 iso-hexane:EtOAc)

2-(6-Methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA28)

Step 1: Preparation ofN-(6-methoxy-5-methylpyridin-3-yl)-2-nitrobenzenesulfonamide

The title compound (2.69 g, 8.32 mmol) was prepared from2-nitrobenzenesulfonyl chloride (2.41 g, 10.9 mmol),6-methoxy-5-methylpyridin-3-amine (1.66 g, 12.0 mmol) and pyridine (2.64mL, 32.7 mmol) in 1,4-dioxane (25 mL) at rt using the methods of(IntA1), step 1.

LCMS (Method B): m/z 324.2 (M+H)⁺ (ES+), at 1.37 min, >95%

Step 2: Preparation of2-amino-N-(6-methoxy-5-methylpyridin-3-yl)benzenesulfonamide

A mixture ofN-(6-methoxy-5-methylpyridin-3-yl)-2-nitrobenzenesulfonamide (2.69 g,8.32 mmol) and 10% palladium on charcoal (1.35 g) in ethanol/EtOAc (1:1,100 mL total reaction volume) was stirred at rt under an atmosphere ofH₂ for approximately 2.5 h. Filtration and concentration in vacuoyielded the crude title compound (2.60 g).

Mass spectroscopy: (ESI+ve) 294.2 [M+H]⁺

Step 3: Preparation of2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide

The title compound was prepared from2-amino-N-(6-methoxy-5-methylpyridin-3-yl)benzenesulfonamide (2.60 g)and triphosgene (815 mg, 2.75 mmol) in anhydrous 1,4-dioxane (160 mL)using the methods of (IntA1) step 3. Concentration in vacuo aftercompletion of the reaction yielded the title compound (3.38 g, 10.6mmol, approximately 80% purity by LCMS) which was used without furtherpurification.

LCMS (Method B): m/z 320.1 (M+H)+ (ES+), at 2.55 min, 80%

2-(5,6-Dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA29)

Steps 1 and 2: Preparation of2-amino-N-(5,6-dimethylpyridin-3-yl)benzenesulfonamide

The title compound (2.7 g, 13.0 mmol) was prepared in two steps from2-nitrobenzenesulfonyl chloride (3.20 g, 14.4 mmol) and5,6-dimethylpyridin-3-amine (1.5 g, 12.3 mmol) in pyridine (20 mL) atrt; followed by SnCl₂ (8.88 g, 46.8 mmol) in ethanol at reflux for 2 husing the methods of (IntA1), steps 1 and 2. Mass spectroscopy: (ESI+ve)277.7 [M+H]⁺

Step 3: Preparation of2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide

The title compound (2.17 g, 7.15 mmol) was prepared from2-amino-N-(5,6-dimethylpyridin-3-yl)benzenesulfonamide (2.7 g, 13.0mmol) and 1,1′-carbonyldiimidazole (4.74 g, 29.2 mmol) in1,2-dichloroethane (25 mL) at 110° C. for 3 h using the methods of(IntA14), step 3.

LCMS (Method B): m/z 304.1 (M+H)+ (ES+), at 1.90 min, 95%

¹H NMR: (400 MHz, CDCl₃) δ: 2.38 (s, 3H), 2.61 (s, 3H), 7.19 (d, J=8.0,1H), 7.35-7.39 (m, 1H), 7.62 (d, J=2.3, 1H), 7.66-7.71 (m, 1H), 7.94(dd, J=7.9, 1.4, 1H), 8.42 (d, J=2.3, 1H), 8.72 (br. s, 1H)

tert-Butyl (6-amino-3-methoxypyridin-2-yl)methylcarbamate (IntA30)

Step 1: Preparation of 6-bromo-3-methoxy-2-nitropyridine

To a stirred solution of 3-hydroxy-2-nitropyridine (50.0 g, 0.34 mol) inMeOH (1 L) was added 30% NaOMe in MeOH (83 mL). The solution was stirredat rt for 30 min then cooled to 0° C. and Br₂ (18 mL, 0.35 mol) wasadded dropwise maintaining this temperature. The reaction was thenstirred at 0° C. for 2 h before the addition of glacial acetic acid (10mL). Concentration in vacuo gave crude material (119 g), to which wasadded acetone (2 L) and K₂CO₃ (153 g, 0.8 mol) followed by iodomethane(85.5 mL, 1.4 mol). After stirring at 40° C. for 4 h the reaction wascooled to rt and filtered. After concentration of the filtrate in vacuopurification by flash chromatography eluting with 3:1 heptane-EtOAcyielded the title compound (14.4 g, 61.8 mmol).

¹H NMR: (400 MHz, CDCl₃) δ: 3.96 (s, 3H), 7.42 (d, J=8.7, 1H), 7.68 (d,J=8.7, 1H)

Step 2: Preparation of 6-bromo-3-methoxypyridin-2-amine

A mixture of 6-bromo-3-methoxy-2-nitropyridine (14.4 g, 61.8 mmol), AcOH(200 mL) and Fe powder (14.0 g, 0.25 mol) was stirred at 90° C. for 1.5h. After cooling to rt and dilution with EtOAc the mixture was filteredthrough celite and the filtrate concentrated in vacuo. Purification byflash chromatography eluting with DCM yielded the title compound (10.2g, 50.2 mmol) as a white solid.

¹H NMR (400 MHz, DMSO) δ: 3.81 (s, 3H), 4.78 (br. s, 2H), 6.73 (d,J=7.8, 2H)

Step 3: Preparation of tert-butyl(6-bromo-3-methoxypyridin-2-yl)carbamate

A mixture of 6-bromo-3-methoxypyridin-2-amine (10.2 g, 50.2 mmol), Boc₂O(38.2 g, 0.18 mol) and 4-(dimethylamino)pyridine (1.2 g, 9.82 mmol) inMeCN (550 mL) was refluxed for 2 h. After cooling to rt andconcentration in vacuo EtOAc (500 mL) was added and the organic phasewashed with water (100 mL) and brine (50 mL). The organic phase wasdried (MgSO₄), filtered and the filtrate concentrated in vacuo.Purification by chromatography eluting with 4:1 DCM-heptane yielded amixture of the title compound and di-tert-butyl(6-bromo-3-methoxypyridin-2-yl)imidodicarbonate (10.6 g) in anapproximate ratio of 55:45.

To a solution of the title compound and di-tert-butyl(6-bromo-3-methoxypyridin-2-yl)imidodicarbonate (7.19 g, approximateratio of 43:57) in MeOH (55 mL) at rt was added K₂CO₃ (7.39 g, 53.5mmol). After stirring at 55° C. for 1.5 h the mixture was cooled to rtand combined with a previous reaction mixture derived from titlecompound and di-tert-butyl(6-bromo-3-methoxypyridin-2-yl)imidodicarbonate (8.83 g, approximateratio of 43:57) and filtered. The residue was washed with EtOAc and thefiltrate was concentrated in vacuo. Purification by gradient flashchromatography, eluting with 10-25% EtOAc in heptane yielded the titlecompound (8.38 g, 27.6 mmol) as a pale yellow solid.

¹H NMR (400 MHz, CDCl₃) δ: 1.52 (s, 9H), 3.85 (s, 3H), 6.94 (d, J=8.2,1H), 7.07 (d, J=8.2, 1H), 7.23 (br. s, 1H)

Step 4: tert-butyl (6-amino-3-methoxypyridin-2-yl)methylcarbamate

NaH (60% in oil, 1.90 g, 47.5 mmol) was added to cooled (5° C.)anhydrous 2-MeTHF (120 mL) under argon, followed by a solution oftert-butyl (6-bromo-3-methoxypyridin-2-yl)carbamate (4.80 g, 15.8 mmol)in anhydrous 2-MeTHF (40 mL) slowly, maintaining the reactiontemperature below 15° C. Once the addition was complete the reaction wasstirred for 15 min prior to addition of iodomethane (2.76 mL, 44.3mmol). After stirring at rt for 21 h, further iodomethane (2.76 mL, 44.3mmol) was added and the reaction mixture stirred at rt for 1 d. Aftercooling to 5° C. saturated aqueous NH₄Cl and H₂O (1:1, 160 mL) was addedwith caution. The mixture was stirred at rt for 15 min, the phases wereseparated and the aqueous phase extracted with EtOAc (2×200 mL). Thecombined organic phases were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo before purification by gradient flashchromatography, eluting with 5-25% EtOAc in heptane yielded tert-butyl(6-bromo-3-methoxypyridin-2-yl)(methyl)carbamate (4.52 g, 14.3 mmol) asa colourless oil. Sodium tert-butoxide (2.74 g, 28.5 mmol), BINAP (355mg, 0.57 mmol) and benzophenone imine (2.63 mL, 15.7 mmol) were added toa solution of tert-butyl(6-bromo-3-methoxypyridin-2-yl)(methyl)carbamate (4.52 g, 14.3 mmol) indegassed toluene (75 mL) under argon. Pd₂(dba)₃ (261 mg, 0.29 mmol) wasadded and the reaction heated at 80° C. for 2 h before cooling to rt andconcentration in vacuo. THF (200 mL) and 0.5 M aqueous HCl (200 mL) wereadded and the mixture was stirred at rt for 1 h then quenched byaddition of saturated aqueous NaHCO₃ (200 mL). After partialconcentration in vacuo to remove the THF, EtOAc (500 mL) was added andthe resulting emulsion was filtered through celite, rinsing with EtOAc.The filtrate layers were separated and the aqueous phase extracted withEtOAc (2×500 mL). The combined organic layers were washed with brine,dried (Na₂SO₄) and concentrated in vacuo before purification by flashchromatography eluting with 1:3 EtOAc in heptane followed by gradientelution with 50-60% EtOAc in heptane with 1% Et₃N yielded impure titlecompound containing BINAP-oxide. 0.5 M aqueous HCl (300 mL) and EtOAc(300 mL) were added, the phases were separated, and the aqueous phasewashed with EtOAc (300 mL). The aqueous phase was then basified withsolid Na₂CO₃ and extracted with EtOAc (3×300 mL). The combined organicphases were washed with brine, dried (Na₂SO₄) and concentrated in vacuoto yield the title compound (2.84 g, 11.21 mmol) as a brown solid.

LCMS (Method B): m/z 254.2 (M+H)+ (ES+), at 2.33 min, 95%

¹H NMR (400 MHz, CDCl₃) δ: 1.39 (s, 9H), 3.16 (s, 3H), 3.74 (s, 3H),4.13 (br. s, 2H), 6.40 (d, J=8.5, 1H), 7.11 (d, 1H)

tert-Butyl[6-(1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl)-3-methoxypyridin-2-yl]methylcarbamate(IntA31)

The title compound (1.03 g, 2.37 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (1.12 g, 5.05 mmol), tert-butyl(6-amino-3-methoxypyridin-2-yl)methylcarbamate (1.41 g, 5.56 mmol) andpyridine (1.23 mL, 15.2 mmol) in DCM (25 mL) at 0° C. to rt; followed by10% Pd/C (895 mg) in EtOAc (40 mL); followed by 1,1′-carbonyldiimidazole(2.65 g, 16.4 mmol) and triethylamine (1.14 mL, 8.18 mmol) in DMF (80mL) using the methods of (IntA17), step 1 and (IntA14), steps 2 and 3.

LCMS (Method B): m/z 435.2 (M+H)+ (ES+), at 2.72 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 1.30 (s, 9H), 3.03 (s, 3H), 3.87 (s, 3H),7.25-7.47 (m, 3H), 7.64 (d, J=8.7, 1H), 7.68-7.79 (m, 1H), 7.84 (dd,J=8.0, 1.1, 1H), 11.57 (s, 1H)

2-(4,5-Dimethoxypyrimidin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA32)

Step 1: Preparation ofN-(4,5-dimethoxypyrimidin-2-yl)-2-nitrobenzenesulfonamide

2-Nitrobenznesulfonyl chloride (649 mg, 2.93 mmol) and4,5-dimethoxypyrimidin-2-amine (500 mg, 3.22 mmol) were dissolved inpyridine (12 mL) and heated at 50° C. overnight. After concentration invacuo purification by gradient flash chromatography, eluting with12-100% EtOAc in iso-hexane yielded the title compound (231 mg, 0.68mmol).

TLC: R_(f)=0.09 (50% EtOAc in iso-hexane)

LCMS (Method A): m/z 339 (M−H)− (ES−), 341 (M+H)+ (ES+), at 0.10 and0.73 min

Steps 2 and 3: Preparation of2-(4,5-dimethoxypyrimidin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide

The title compound was prepared in two steps fromN-(4,5-dimethoxypyrimidin-2-yl)-2-nitrobenzenesulfonamide (231 mg, 0.68mmol), Fe powder (380 mg, 6.8 mmol) and acetic acid (5 mL); followed by1,1′-carbonyldiimidazole (396 mg, 2.44 mmol) and triethylamine (0.17 mL,1.22 mmol) in DMF (4.0 mL) using the methods of (IntA17), step 2 and(IntA14), step 3. The residue from step 3 was triturated with Et₂O toyield the title compound (104 mg, 0.31 mmol).

LCMS (Method A): m/z 335 (M−H)− (ES−), 337 (M+H)+ (ES+), at 0.11 and1.01 min

2-(4,6-Dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA33)

The title compound (316 mg, 0.94 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (2.15 g, 9.7 mmol),4,6-dimethoxypyridin-2-amine hydrochloride (2.04 g, 10.7 mmol) andpyridine (2.35 mL, 29.1 mmol) in DCM (35 mL) at rt; followed by Fepowder (1.38 g, 24.7 mmol) and acetic acid (15 mL); followed by1,1′-carbonyldiimidazole (1.62 g, 10.0 mmol) and triethylamine (0.70 mL,5.0 mmol) in DMF (10.0 mL) using the methods of (IntA1), step 1,(IntA17), step 2 and (IntA14), step 3.

LCMS (Method B): m/z 334 (M−H)− (ES−), 336 (M+H)+ (ES+), at 1.91 min,100%.

¹H NMR: (400 MHz, DMSO) δ: 3.77 (s, 3H), 3.81 (s, 3H), 6.50 (d, J=1.8,1H), 6.71 (d, J=1.8, 1H), 7.26-7.39 (m, 2H), 7.68-7.78 (m, 1H),7.80-7.88 (m, 1H), 11.60 (br. s, 1H)

tert-Butyl (5-amino-2-methoxypyridin-3-yl)methylcarbamate (IntA34)

Steps 1 to 3: Preparation of N-(2-methoxy-5-nitropyridin-3-yl)acetamide

A solution of 2-methoxy-3-nitropyridine (50 g, 324.4 mmol) and 10% Pd/C(5 g) in MeOH (500 mL) was stirred under an atmosphere of H₂ for 3 h.The mixture was filtered through celite and the filter was washed withMeOH. The filtrate was concentrated in vacuo to yield2-methoxypyridin-3-amine as a brown solid (38.9 g, 313.4 mmol).

¹H NMR: (300 MHz, CDCl₃) δ: 3.74 (br. s, 2H), 3.96 (s, 3H), 6.72 (m,1H), 6.86 (m, 1H), 7.56 (d, J=1.8, 1H)

To a stirred solution of 2-methoxypyridin-3-amine (20 g, 161.1 mmol) andDIPEA (29.5 mL, 169.2 mmol) in DCM (120 mL) was added acetic anhydride(16 mL, 169.2 mmol) slowly. The reaction was then stirred at rt for 2 hbefore water (50 mL) was added and the phases were separated. The DCMlayer was then washed with brine (20 mL), dried (MgSO₄) and concentratedin vacuo to yield a brown solid (26 g), which upon trituration withheptane gave N-(2-methoxypyridin-3-yl)acetamide as a beige solid (24 g,144.4 mmol).

¹H NMR: (400 MHz, CDCl₃) δ: 2.15 (s, 3H), 4.04 (s, 3H), 6.88 (m, 1H),7.65 (br. s, 1H), 7.82 (m, 1H), 8.55 (d, J=1.8, 1H)

To a stirred solution of N-(2-methoxypyridin-3-yl)acetamide (23 g, 139mmol) in trifluoroacetic anhydride (TFAA) (90 mL) was added a solutionof HNO₃ (5.84 mL, 139 mmol) in TFAA (140 mL) dropwise at rt. Thereaction was stirred for 1.5 h at rt before being poured into an icebath with stirring. The precipitated solid was filtered and washed withEt₂O (50 mL), then dissolved in EtOAc (1 L) and washed with saturatedaqueous NaHCO₃ (100 mL) and brine (100 mL). The phases were separatedand the organic phase dried (MgSO₄), and concentrated in vacuo to yieldthe title compound as a light yellow solid (21.2 g, 100.4 mmol).

¹H NMR: (400 MHz, CDCl₃) δ: 2.25 (s, 3H), 4.11 (s, 3H), 7.67 (br. s,1H), 8.76 (d, J 2.8, 1H), 9.37 (d, J=2.8, 1H)

Steps 4 to 7: Preparation of tert-butyl(5-amino-2-methoxypyridin-3-yl)methylcarbamate

To a stirred solution of N-(2-methoxy-5-nitropyridin-3-yl)acetamide (14g, 66.7 mmol) in MeCN (600 mL) was added Boc-anhydride (36.4 mL, 166.7mmol) followed by 4-(dimethylamino)pyridine (1.6 g, 13.4 mmol). Afterstirring at reflux for 5 h the mixture was concentrated in vacuo and theresidue redissolved in EtOAc (300 mL) and washed with water (50 mL) andbrine (50 mL), dried (MgSO₄) and concentrated in vacuo. Purification byflash column chromatography eluting with 4:1 DCM-heptane yieldedtert-butyl acetyl(2-methoxy-5-nitropyridin-3-yl)carbamate as a lightyellow solid (18.3 g, 58.8 mmol.

¹H NMR: (400 MHz, CDCl₃) δ: 1.38 (s, 9H), 2.64 (s, 3H), 4.09 (s, 3H),8.17 (s, 1H), 9.05 (s, 1H)

To a stirred solution of tert-butylacetyl(2-methoxy-5-nitropyridin-3-yl)carbamate (18.3 g, 58.9 mmol) inMeCN (450 mL) was added N,N-diethylethylenediamine (13.7 g, 117.8 mmol).After stirring at rt for 16 h the precipitated solids were isolated byfiltration and washed with heptanes to yield a light yellow solid (4.1g). The filtrate was concentrated in vacuo, cooled in an ice-bath andfurther solid precipitated from the solution. The solids were isolatedby filtration and washed with heptanes to give another batch of lightyellow solid. The two batches were combined to afford tert-butyl(2-methoxy-5-nitropyridin-3-yl)carbamate (12.2 g, 45.3 mmol).

¹H NMR: (400 MHz, CDCl₃) δ: 1.54 (s, 9H), 4.16 (s, 3H), 7.03 (br. s,1H), 8.17 (s, 1H), 9.08 (s, 1H)

To a stirred solution of tert-butyl(2-methoxy-5-nitropyridin-3-yl)carbamate (12.2 g, 45.3 mmol) inanhydrous THF (400 mL) was added NaH (60% in mineral oil, 3.6 g, 90.8mmol) at 0° C. and the mixture was stirred at 0° C. for 15 min. Asolution of iodomethane (5.7 mL, 90.8 mmol) in THF (50 mL) was addeddropwise to the mixture which was then warmed to rt and stirred for 16h. After careful quenching with saturated aqueous NH₄Cl solids wereremoved by filtration and the filtrate was diluted with EtOAc (400 mL).The organic phase was washed with water and brine, dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatographyeluting with 4:1 DCM-heptane yielded tert-butyl(2-methoxy-5-nitropyridin-3-yl)methylcarbamate (9.8 g, 34.6 mmol) as ayellow solid.

¹H NMR: (400 MHz, CDCl₃) δ: 1.39 (s, 9H), 3.15 (s, 3H), 4.08 (s, 3H),8.23 (s, 1H), 8.96 (s, 1H)

10% Pd/C (1 g) was added to a solution of tert-butyl(2-methoxy-5-nitropyridin-3-yl)methylcarbamate (9.8 g, 34.6 mmol) inMeOH (150 mL) and DCM (75 mL) and the mixture stirred at rt for 7 hunder an atmosphere of H₂. The reaction mixture was then filteredthrough celite and washed with MeOH and the filtrate concentrated invacuo. Purification by flash column chromatography eluting with 2:1 to1:1 heptane-EtOAc yielded the title compound (7.4 g, 29.2 mmol) as a tansolid.

¹H NMR: (400 MHz, CDCl₃) δ: 1.38 (s, 9H), 3.08 (s, 3H), 3.35 (br. s,2H), 3.87 (s, 3H), 6.91 (s, 1H), 7.55 (s, 1H)

tert-Butyl[5-(1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl)-2-methoxypyridin-3-yl]methylcarbamate(IntA35)

The title compound (2.12 g, 4.84 mmol) was prepared in three steps from2-nitrobenzenesulfonyl chloride (1.11 g, 5.0 mmol), tert-butyl(5-amino-2-methoxypyridin-3-yl)methylcarbamate (IntA34) (1.39 g, 5.5mmol) and pyridine (1.21 mL, 15.0 mmol) in 1,4-dioxane (20 mL); followedby followed by 10% Pd/C (212 mg) in water/EtOH (1:1, 100 mL); followedby 1,1′-carbonyldiimidazole (1.14 g, 7.02 mmol) and triethylamine (0.49mL, 3.51 mmol) in DMF (8 mL) using the methods of (IntA1), step 1 and(IntA14), steps 2 and 3.

LCMS (Method B): m/z 433 (M−H)− (ES−), 435 (M+H)+ (ES+), at 3.03 min,100%

¹H NMR: (400 MHz, DMSO) δ: 1.30 (s, 9H), 3.02 (s, 3H), 3.93 (s, 3H),7.24-7.38 (m, 2H), 7.66-7.77 (m, 2H), 7.83-7.94 (m, 1H), 8.09 (s, 1H),11.66 (br. s, 1H)

Route 22-[(2-Chloro-6-fluorobenzyl)amino]-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzenesulfonamide(IntB1)

Step 1: Preparation of2-Fluoro-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzenesulfonamide

2-Fluorobenzenesulfonyl chloride (0.46 mL, 3.5 mmol) was added to asolution of 5-amino-1-methyl-1,2-dihydropyridin-2-one (478 mg, 3.85mmol) in 1,4-dioxane (10 mL) and stirred for 28 h at rt. Afterconcentration in vacuo purification by column chromatography elutingwith DCM:MeOH:7M NH₃ in MeOH (90:5:5) yielded the title compound (448mg, 1.59 mmol).

LCMS (Method A): m/z 283 (M+H)+ (ES+), at 0.13 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.35 (s, 3H), 6.26 (d, J=9.5, 1H), 7.03 (dd,J=9.7, 2.9, 1H), 7.30-7.40 (m, 1H), 7.47 (dd, J=10.0, 8.5, 1H), 7.52 (d,J=3.0, 1H), 7.65-7.79 (m, 2H), 9.96 (s, 1H)

Step 2: Preparation of2-[(2-chloro-6-fluorobenzyl)amino]-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzenesulfonamide(IntB1)

A mixture of2-fluoro-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzenesulfonamide(72 mg, 0.26 mmol) and 2-chloro-6-fluorobenzyl amine (0.33 mL, 2.6 mmol)in MeCN (1.5 mL) was heated at 180° C. for 6 h in a Biotage Initiatormicrowave reactor. After concentration in vacuo purification by gradientcolumn chromatography eluting with 0-10% MeOH in DCM yielded impuretitle compound (151 mg) which was used without further purification.

LCMS (Method A): m/z 422.0, 423.9 (M+H)+ (ES+), at 0.13 and 1.11 min,60%.

TLC: Rf=0.91 (DCM:MeOH, 9:1)

2-[(2-Chloro-6-fluorobenzyl)amino]-N-(2-methoxypyrimidin-5-yl)benzenesulfonamide(IntB2)

The title compound (106 mg, impure, used without further purification)was prepared in two steps from 2-fluorobenzenesulfonyl chloride (0.46mL, 3.5 mmol) and 5-amino-2-methoxypyrimidine (482 mg, 3.85 mmol) in1,4-dioxane at 100° C.; followed by 2-chloro-6-fluorobenzyl amine (0.36mL, 2.8 mmol) in MeCN (1.5 mL) at 180° C. in a Biotage Initiatormicrowave reactor using the methods of (IntB1).

LCMS (Method A): m/z 421.2, 423.2 (M−H)− (ES−), at 0.13 and 1.13 min,95%

TLC: Rf=0.64 (iso-hexane:EtOAc)

5-Fluoro-2-{[1-(2-fluorophenyl)ethyl]amino}-N-[3-(methylsulfanyl)phenyl]benzenesulfonamide(IntB3)

The title compound (139 mg, 0.32 mmol) was prepared in two steps from2,5-difluorobenzenesulfonyl chloride (1.07 g, 5.0 mmol) and3-(methylsulfanyl)aniline (769 mg, 5.5 mmol) in 1,4-dioxane at 70° C.;followed by 1-(2-fluorophenyl)ethanamine (500 mg, 3.6 mmol) in MeCN (0.5mL) at 200° C. in a Biotage Initiator microwave reactor using themethods of (IntB1).

LCMS (Method B): m/z 435 (M+H)+ (ES+), at 3.50 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 1.52 (d, J=6.5, 3H), 2.39 (s, 3H), 4.86(quin, J=6.5, 1H), 6.09 (d, J=5.8, 1H), 6.41 (dd, J=9.3, 4.3, 1H),6.85-7.08 (m, 4H), 7.13-7.31 (m, 5H), 7.43 (dd, J=8.7, 3.1, 1H), 10.84(s, 1H)

2-[(2-Chloro-6-fluorobenzyl)amino]-5-fluoro-N-[3-(methylsulfanyl)phenyl]benzenesulfonamide(IntB4)

The title compound (119 mg, 0.26 mmol) was prepared in two steps from2,5-difluorobenzenesulfonyl chloride (1.07 g, 5.0 mmol) and3-(methylsulfanyl)aniline (769 mg, 5.5 mmol) in 1,4-dioxane at 70° C.;followed by 2-chloro-6-fluorobenzyl amine (762 uL, 5.9 mmol) in MeCN(1.5 mL) at 180° C. in a Biotage Initiator microwave reactor using themethods of (IntB1).

LCMS (Method B): m/z 455, 457 (M+H)+ (ES+), at 3.45 min, >95%

TLC: Rf=0.52 (1:4 EtOAc:iso-hexane)

2-[(2-Chloro-6-fluorobenzyl)amino]-3-fluoro-N-(6-methoxypyridin-3-yl)benzenesulfonamide(IntB5)

The title compound (139 mg, 0.32 mmol) was prepared in two steps from2,3-difluorobenzenesulfonyl chloride (1.0 g, 4.7 mmol) and6-methoxypyridin-3-amine (642 mg, 5.2 mmol) in 1,4-dioxane at 100° C.;followed by 2-chloro-6-fluorobenzyl amine (547 mg, 3.4 mmol) in MeCN (3mL) at 180° C. in a Biotage Initiator microwave reactor using themethods of (IntB1).

LCMS (Method B): m/z 439.9, 441.9 (M+H)+ (ES+), at 2.35 min, 95%

3-Fluoro-N-(6-methoxypyridin-3-yl)-2-[(2-methylbenzyl)amino]benzenesulfonamide(IntB6)

The title compound (139 mg, 0.35 mmol) was prepared in two steps from2,3-difluorobenzenesulfonyl chloride (1.0 g, 4.7 mmol) and6-methoxypyridin-3-amine (642 mg, 5.2 mmol) in 1,4-dioxane at 100° C.;followed by 2-methylbenzyl amine (425 uL, 3.4 mmol) in MeCN (3 mL) at180° C. in a Biotage Initiator microwave reactor using the methods of(IMB1).

LCMS (Method B): m/z 402.0 (M+H)+ (ES+), at 2.38 min, 95%

Route 4 2-Chloro-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide (IntC1)

A solution of 2-chloropyridine-3-sulfonyl chloride (500 mg, 2.36 mmol)and 3,4-dimethoxyaniline (397 mg, 2.59 mmol) in 1,4-dioxane (10 mL) wasstirred for 1 h at 0° C. The reaction mixture was filtered, the residuewashed with ether and the filtrate concentrated in vacuo. Purificationby gradient column chromatography eluting with 10-60% EtOAc iniso-hexane yielded the title compound (352 mg, 1.07 mmol).

LCMS (Method A): m/z 327.2, 329.1 (M−H)− (ES−), at 0.12 min, 95%

¹H NMR: (400 MHz, DMSO) δ 3.64 (s, 3H), 3.65 (s, 3H), 6.59 (dd, J=8.7,2.4, 1H), 6.72 (d, J=2.5, 1H), 6.80 (d, J=8.5, 1H), 7.59 (dd, J=7.8,4.8, 1H), 8.36 (dd, J=7.8, 1.8, 1H), 8.61 (dd, J=4.8, 1.8, 1H), 10.53(s, 1H)

2-Chloro-N-(2,6-dimethoxypyridin-4-yl)pyridine-3-sulfonamide (IntC2)

The title compound (623 mg, 1.89 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol),2,6-dimethoxy-4-pyridinamine (424 mg, 2.8 mmol) and pyridine (0.6 mL,7.5 mmol) in DCM (10 mL) using the methods of (IntC1).

LCMS (Method A): m/z 328, 330 (M−H)− (ES−), 330, 332 (M+H)+ (ES+), at0.13 and 0.73 min, 60%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 6H), 6.03 (s, 2H), 7.71 (dd, J=7.8,4.8, 1H), 8.58 (dd, J=7.8, 1.8, 1H), 8.68 (dd, J=4.8, 1.8, 1H), 11.54(br s, 1H)

2-Chloro-N-(5,6-dimethoxypyridin-2-yl)pyridine-3-sulfonamide (IntC3)

The title compound (549 mg, 1.66 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol),5,6-dimethoxypyridin-2-amine (424 mg, 2.8 mmol) and pyridine (0.6 mL,7.5 mmol) in DCM (10 mL) using the methods of (IntC1).

LCMS (Method A): m/z 328, 330 (M−H)− (ES−), 330, 332 (M+H)+ (ES+), at0.12 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.42 (s, 3H), 3.68 (s, 3H), 6.52 (d, J=8.3,1H), 7.26 (d, J=8.3, 1H), 7.67 (dd, J=7.8, 4.8, 1H), 8.58 (dd, J=7.9,1.9, 1H), 8.64 (dd, J=4.8, 1.8, 1H), 11.22 (s, 1H)

2-Chloro-N-(5,6-dimethoxypyridin-3-yl)pyridine-3-sulfonamide (IntC4)

The title compound (542 mg, 1.64 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol),5,6-dimethoxypyridin-3-amine (424 mg, 2.8 mmol) and pyridine (0.6 mL,7.5 mmol) in DCM (10 mL) using the methods of (IntC1).

LCMS (Method A): m/z 328, 330 (M−H)− (ES−), 330, 332 (M+H)+ (ES+), at0.12 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 3.70 (s, 3H), 3.77 (s, 3H), 7.02 (d, J=2.3,1H), 7.39 (d, J=2.3, 1H), 7.61 (dd, J=8.0, 4.8, 1H), 8.38 (dd, J=7.8,1.8, 1H), 8.64 (dd, J=4.8, 1.8, 1H), 10.71 (s, 1H)

2-Chloro-N-(3,4-dimethylphenyl)pyridine-3-sulfonamide (IntC5)

The title compound (966 mg, 3.26 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (1.11 g, 5.21 mmol) and3,4-dimethylaniline (698 mg, 5.73 mmol) in 1,4-dioxane (30 mL) using themethods of (IntC1).

LCMS (Method B): m/z 295.3, 297.2 (M−H)− (ES−), at 1.38 min, 80%.

¹H NMR: (400 MHz, DMSO) δ 2.09 (s, 3H), 2.10 (s, 3H), 6.83 (dd, J=8.0,2.0, 1H), 6.89 (d, J=1.8, 1H), 6.98 (d, J=8.0, 1H), 7.60 (dd, J=7.9,4.9, 1H), 8.39 (dd, J=7.8, 1.8, 1H), 8.60 (dd, J=4.8, 2.0, 1H), 10.61(s, 1H)

2-Chloro-N-(3,5-dimethylphenyl)pyridine-3-sulfonamide (IntC6)

The title compound (791 mg, 2.67 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (1.09 g, 5.12 mmol) and3,5-dimethylaniline (709 uL, 5.65 mmol) in 1,4-dioxane (30 mL) using themethods of (IntC1).

LCMS (Method B): m/z 295.3, 297.2 (M−H)− (ES−), at 1.38 min, 80%.

¹H NMR: (400 MHz, DMSO) δ 2.09 (s, 3H), 2.10 (s, 3H), 6.83 (dd, J=8.0,2.0, 1H), 6.89 (d, J=1.8, 1H), 6.98 (d, J=8.0, 1H), 7.60 (dd, J=7.9,4.9, 1H), 8.39 (dd, J=7.8, 1.8, 1H), 8.60 (dd, J=4.8, 2.0, 1H), 10.61(s, 1H)

tert-Butyl (6-amino-2-methoxypyridin-3-yl)methylcarbamate (IntC7)

Step 1: Preparation of tert-butyl(6-bromo-2-methoxypyridin-3-yl)carbamate

To a stirred solution of 6-bromo-2-methoxypyridin-3-amine (6.27 g, 30.9mmol) in MeCN (70 mL) at rt was added Boc₂O (14.8 g, 67.9 mmol). Theresulting solution was stirred at 70° C. for 20 h before cooling to rtand the addition of further Boc₂O (14.8 g, 67.9 mmol). After stirring at70° C. for 21 h the mixture was cooled to rt, further Boc₂O (14.8 g,67.9 mmol) was added and the reaction was stirred at 70° C. for 23 h.After cooling to rt excess Boc₂O was destroyed by portion-wise additionof imidazole (23.5 g, 346 mmol) and the mixture stirred vigorously for15 min. Silica gel (210 mL) was added and the mixture concentrated invacuo. Purification by gradient column chromatography eluting with 2-5%EtOAc in heptane yielded the title compound (7.07 g, 23.3 mmol) as a redoil.

¹H NMR: (400 MHz, CDCl₃) δ: 1.51 (s, 9H), 3.99 (s, 3H), 6.86 (br. s,1H), 7.01 (d, J=8.0, 1H), 8.17 (br. d, J=8.0, 1H)

Step 2: Preparation of tert-butyl(6-amino-2-methoxypyridin-3-yl)methylcarbamate

The title compound was prepared from tert-butyl(6-bromo-2-methoxypyridin-3-yl)carbamate (7.07 g, 23.3 mmol) andiodomethane (6.17 mL, 98.0 mmol); followed by sodium tert-butoxide (2.17g, 22.6 mmol), BINAP (1.41 g, 2.26 mmol), benzophenone imine (2.08 mL,12.4 mmol), tert-butyl (6-bromo-2-methoxypyridin-3-yl)(methyl)carbamate(3.58 g, 11.3 mmol) and Pd₂(dba)₃ (1.03 g, 1.13 mmol) in toluene (60 mL)at 80° C. using the methods of (IntA30), step 4. Combination withbatches of material derived from tert-butyl(6-bromo-2-methoxypyridin-3-yl)(methyl)carbamate (3.24 g and 576 mg)before purification using the methods of (IntA30), step 4 yielded thetitle compound (5.83 g, 23.0 mmol).

LCMS (Method B): m/z 254.2 (M+H)+ (ES+), at 2.92 min, 95%

¹H NMR: (400 MHz, CDCl₃) δ: 1.49, 1.33 (br. s, 9H, rotamers), 3.05 (s,3H), 3.85 (s, 3H), 4.25 (br. s, 2H), 6.00 (J=8.0, 1H), 7.13 (d, J=8.0,1H)

tert-Butyl(6-{[(2-chloropyridin-3-yl)sulfonyl]amino}-2-methoxypyridin-3-yl)methylcarbamate(IntC8)

The title compound (1.51 g, 3.53 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (1.16 g, 5.48 mmol), tert-butyl(6-amino-2-methoxypyridin-3-yl)methylcarbamate (IntC7) (1.53 g, 6.03mmol) and pyridine (1.33 mL, 16.4 mmol) in DCM (20 mL) at rt using themethods of (IntC1).

LCMS (Method B): m/z 429.2, 431.2 (M+H)+ (ES+), at 1.67 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 1.16 (s, 6H), 1.35 (s, 3H), 2.87 (s, 3H),3.40 (s, 3H), 6.46 (d, J=8.2, 1H), 7.46 (d, J=7.8, 1H), 7.65 (dd, J=7.3,5.0, 1H), 8.57-8.64 (m, 2H), 11.64 (br. s, 1H)

N-(1,3-Benzothiazol-6-yl)-2-chloropyridine-3-sulfonamide (IntC9)

The title compound (1.1 g, 3.38 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (1.56 g, 7.36 mmol),1,3-benzothiazol-6-amine (1.0 g, 6.66 mmol) and pyridine (10 mL) at rtusing the methods of (IntC1).

Mass spectroscopy: (ESI+ve) 326.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 7.30 (d, J=8.9, 1H), 7.61 (dd, J=7.6, 4.9,1H), 7.89 (s, 1H), 7.97 (d, J=8.6, 1H), 8.48 (d, J=7.9, 1H), 8.60 (d,J=4.9, 1H), 9.28 (s, 1H), 11.17 (s, 1H)

6-Methoxy-5-methylpyridin-2-amine (IntC10)

Step 1: Preparation of 2-acetamido-5-methylpyridine N-oxide

m-CPBA (75% in H₂O, 89.6 g, 390 mmol) was added portion wise to astirred solution of N-(5-methylpyridin-2-yl)acetamide (45.0 g, 300 mmol)in DCM (2.7 L) at rt, and the mixture stirred at rt for 4 h. 5% aqueousNa₂SO₃ (200 mL) was added slowly, the phases were separated and theorganic layer washed with saturated NaHCO₃, brine (100 mL), dried(MgSO₄) and filtered. After concentration in vacuo purification bygradient column chromatography eluting with 2-5% MeOH in DCM yielded thetitle compound (37.5 g, 243 mmol) as a pale yellow solid.

¹H NMR: (400 MHz, CDCl₃) δ: 2.26 (s, 6H), 7.14 (J=8.7, 1H), 8.06 (s,1H), 8.30 (d, J=8.7, 1H), 9.87 (br. s, 1H)

Step 2: Preparation of N-(6-methoxy-5-methylpyridin-2-yl)acetamide

A solution of 2-acetamido-5-methylpyridine N-oxide (28.2 g, 170 mmol) inacetic anhydride (840 mL) was stirred at 70° C. for 4 h. After coolingto rt and concentration in vacuo Et₂O (180 mL) was added and theresulting solids isolated by filtration and washed with MeOH to give6-acetamido-3-methylpyridin-2-yl acetate (6.87 g, 33.0 mmol) as a palebrown solid.

¹H NMR: (400 MHz, CDCl₃) δ: 2.14 (s, 3H), 2.15 (s, 3H), 2.32 (s, 3H),7.59 (d, J=8.0, 1H), 7.80 (br. s, 1H), 8.02 (d, J=8.0, 1H)

To a stirred solution of 6-acetamido-3-methylpyridin-2-yl acetate (3.44g, 16.5 mmol) in 2:1 MeOH/DCM (105 mL) at rt was added Ag₂CO₃ (9.11 g,33.0 mmol) followed by iodomethane (3.09 mL, 49.6 mmol). The resultingmixture was stirred at 35° C. for 18 h then stood at rt for 2 d. Thereaction mixture was combined with 2 previous batches derived from6-acetamido-3-methylpyridin-2-yl acetate (590 mg, 2.83 mmol and 3.44 g,16.5 mmol) and the combined batches were filtered through celite,rinsing with DCM. After concentration of the filtrate in vacuopurification by gradient column chromatography eluting with 20-50% EtOAcin heptane yielded the title compound (4.27 g, 23.7 mmol) as a whitesolid.

¹H NMR: (400 MHz, CDCl₃) δ: 2.12 (s, 3H), 2.18 (s, 3H), 3.85 (s, 3H),7.36 (d, J=7.8, 1H), 7.59 (br. s, 1H), 7.60 (d, J=7.8, 1H)

Step 3: Preparation of 6-methoxy-5-methylpyridin-2-amine

A 10% solution of aqueous NaOH (40 mL) was added to a solution ofN-(6-methoxy-5-methylpyridin-2-yl)acetamide (2.21 g, 12.3 mmol) in MeOH(160 mL) and the reaction mixture was heated at 90° C. for 3 d. Aftercooling to rt and concentration in vacuo to remove the MeOH the aqueousresidue was combined with that from a previous batch derived fromN-(6-methoxy-5-methylpyridin-2-yl)acetamide (2.21 g, 12.3 mmol). Theaqueous phase was diluted with H₂O (40 mL) and extracted with DCM (3×150mL). The combined organic phases were washed with brine, dried (Na₂SO₄)and combined with a previous batch of crude6-methoxy-5-methylpyridin-2-amine (266 mg). Concentration in vacuoyielded the title compound (3.30 g, 23.9 mmol).

LCMS (Method B): m/z 139.1 (M+H)+ (ES+), at 1.81 min, 95%

¹H NMR: (400 MHz, CDCl₃) δ: 2.04 (s, 3H), 3.86 (s, 3H), 4.11 (br. s,2H), 5.98 (d, J=7.8, 1H), 7.14 (d, J=7.8, 1H)

2-Chloro-N-(6-methoxy-5-methylpyridin-2-yl)pyridine-3-sulfonamide(IntC11)

The title compound (1.60 g, 5.10 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (1.35 g, 6.39 mmol),6-methoxy-5-methylpyridin-2-amine (IntC10) (970 mg, 7.02 mmol) andpyridine (1.55 mL, 19.2 mmol) in 1,4-dioxane (25 mL) at rt using themethods of (IntC1).

LCMS (Method B): m/z 314.1, 316.1 (M+H)+ (ES+), at 0.11, 0.89 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 1.93 (s, 3H), 3.38 (s, 3H), 6.40 (d, J=7.8,1H), 7.38 (d, J=7.8, 1H), 7.64 (dd, J=7.8, 5.0, 1H), 8.49-8.69 (m, 2H),11.40 (br. s, 1H)

tert-Butyl (5-amino-3-methylpyridin-2-yl)methylcarbamate (IntC12)

Step 1: Preparation of tert-butylmethyl(3-methyl-5-nitropyridin-2-yl)carbamate

2-Chloro-3-methyl-5-nitropyridine (5.00 g, 29.0 mmol) was added portionwise to a cooled (0° C.) 35% solution of methylamine in EtOH (20 mL) andthe reaction was allowed to warm to rt. After approximately 5 min anexotherm and gas evolution was observed and the reaction mixturesolidified. EtOH (10 mL) was added and the reaction mixture was stirredat rt for 20 min, then diluted with ice/water (30 mL) and cooled to 0°C. The mixture was stirred vigorously for 15 min and then allowed tostand for 17 h. A solid was isolated by filtration, washed with H₂O anddried in vacuo to yield N,3-dimethyl-5-nitropyridin-2-amine (4.44 g)which was used without further purification. A mixture ofN,3-dimethyl-5-nitropyridin-2-amine (4.44 g, 26.6 mmol), Boc₂O (11.6 g,53.1 mmol) and 4-(dimethylamino)pyridine (649 mg, 5.31 mmol) in MeCN(230 mL) was stirred at 75° C. for 21 h. Further Boc₂O (2.32 g, 10.6mmol) was added and heating at 75° C. was continued for 24 h, beforecooling to rt. Imidazole (5.06 g, 74.4 mmol) was added and the mixtureconcentrated in vacuo. Purification by gradient flash chromatographyeluting with 5-20% EtOAc in heptane yielded the title compound (6.20 g,23.2 mmol) as a yellow oil which solidified upon standing.

¹H NMR: (400 MHz, CDCl₃) δ: 1.45 (s, 9H), 2.35 (s, 3H), 3.30 (s, 3H),8.31 (d, J=2.3, 1H), 9.11 (d, J=2.3, 1H)

Step 2: Preparation of tert-butyl(5-amino-3-methylpyridin-2-yl)methylcarbamate

10% Pd/C (320 mg) was added to a solution of tert-butylmethyl(3-methyl-5-nitropyridin-2-yl)carbamate (3.20 g, 12.0 mmol) in 4:1MeOH/DCM (100 mL) and the mixture stirred at rt under an atmosphere ofH₂ for 3 h. The reaction mixture was filtered through celite, washingwith 15:85 MeOH/DCM (100 mL) and the filtrate was combined with 2.88 gof a previously prepared batch of crude product. After concentration invacuo purification by flash chromatography eluting with 100% EtOAcyielded the title compound (5.27 g, 22.2 mmol) as a brown solid.

LCMS (Method B): m/z 238.2 (M+H)+ (ES+), at 2.33 min, 95%

¹H NMR: (400 MHz, CDCl₃) δ: 1.34, 1.49 (br. s, 9H), 2.13 (s, 3H), 3.15(s, 3H), 3.62 (br. s, 2H), 6.85 (d, J=2.9, 1H), 7.76 (d, J=2.9, 1H)

tert-Butyl(5-{[(2-chloropyridin-3-yl)sulfonyl]amino}-3-methylpyridin-2-yl)methylcarbamate(IntC13)

The title compound (1.98 g) was prepared from2-chloropyridine-3-sulfonyl chloride (910 mg, 4.29 mmol), tert-butyl(5-amino-3-methylpyridin-2-yl)methylcarbamate (IntC12) (1.12 g, 4.72mmol) and pyridine (1.04 mL, 12.9 mmol) in DCM (25 mL) at rt using themethods of (IntC1).

LCMS (Method B): m/z 413.0 (M+H)+ (ES+), at 1.66 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 1.26 (br. s, 9H), 2.04-2.14 (m, 3H), 3.02 (s,3H), 7.42 (d, J=2.3, 1H), 7.64 (dd, J=7.8, 4.8, 1H), 8.03 (d, J=2.8,1H), 8.49 (dd, J=7.8, 1.8, 1H), 8.64 (dd, J=4.8, 1.8, 1H), 11.14 (s, 1H)

2-Chloro-N-(5-methoxy-6-methylpyridin-3-yl)pyridine-3-sulfonamide(IntC14)

The title compound (117 mg, 0.372 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (469 mg, 2.2 mmol),5-methoxy-6-methylpyridin-3-amine (336 mg, 2.4 mmol) and pyridine (0.54mL, 7.5 mmol) in DCM (9 mL) at 0° C. to rt using the methods of (IntC1).

LCMS (Method B): m/z 312, 314 (M−H)− (ES−), 314, 316 (M+H)+ (ES+), at0.10 min, 80%

¹H NMR: (400 MHz, DMSO) δ: 2.24 (s, 3H), 3.74 (s, 3H), 7.05 (d, J=1.8,1H), 7.64 (dd, J=7.8, 4.6, 1H), 7.77 (d, J=1.8, 1H), 8.48 (dd, J=8.2,1.8, 1H), 8.65 (dd, J=4.6, 1.8, 1H), 11.03 (br. s, 1H)

tert-Butyl(5-{[(2-chloropyridin-3-yl)sulfonyl]amino}-2-methoxypyridin-3-yl)methylcarbamate(IntC15)

The title compound (2.12 g, 4.94 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-2-methoxypyridin-3-yl)methylcarbamate (IntA34) (1.45 g, 5.72mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using themethods of (IntC1).

LCMS (Method B): m/z 427, 429 (M−H)− (ES−), 429, 431 (M+H)+ (ES+), at0.10 and 1.44 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 1.20 (s, 9H), 2.89 (s, 3H), 3.77 (s, 3H),7.29 (s, 1H), 7.57 (dd, J=6.9, 5.0, 1H), 7.76 (s, 1H), 8.33 (d, J=7.8,1H), 8.59 (d, J=2.7, 1H), 10.76 (br. s, 1H)

tert-Butyl (5-amino-3-methoxypyridin-2-yl)methylcarbamate (IntC16)

Step 1: Preparation of tert-butyl(3-methoxy-5-nitropyridin-2-yl)methylcarbamate

2-Chloro-3-methoxy-5-nitropyridine (8.00 g, 43.4 mmol) was addedportion-wise to a 35% solution of methylamine in EtOH (14 mL). Afterstanding for 10 min the mixture was cooled to 0° C. and further 35%methylamine in EtOH (14 mL) was added. After stirring at rt for 20 minice/water (˜28 mL) was added. The mixture was cooled to 0° C., stirredvigorously and then allowed to stand for 15 min. The resulting solidswere isolation by filtration, washed with H₂O and dried to yield crude3-methoxy-N-methyl-5-nitropyridin-2-amine (7.81 g) which was usedwithout further purification.

¹H NMR: (400 MHz, CDCl₃) δ: 3.13 (d, J=5.0, 3H), 3.92 (s, 3H), 5.71 (br.s, 1H), 7.52 (d, J=2.3, 1H), 8.76 (d, J=2.3, 1H)

3-Methoxy-N-methyl-5-nitropyridin-2-amine (7.81 g, 42.6 mmol) wassuspended in DCM (400 mL) at rt and Boc₂O (10.2 g, 46.9 mmol) followedby 4-(dimethylamino)pyridine (365 mg, 2.98 mmol) were added. Afterstirring at rt for 19 h, then 40° C. for 2 h, the mixture was cooled andconcentrated in vacuo. MeCN (370 mL), Boc₂O (10.2 g, 46.9 mmol) followedby 4-(dimethylamino)pyridine (780 mg, 6.38 mmol) were added and thesolution stirred at 75° C. for 3 d. After concentration in vacuopurification by gradient flash chromatography eluting with 5-35% EtOAcin heptane yielded the title compound (10.3 g, 36.4 mmol) as a yellowsolid.

¹H NMR: (400 MHz, CDCl₃) δ: 1.41 (s, 9H), 3.30 (s, 3H), 3.93 (s, 3H),7.91 (d, J=2.3, 1H), 8.88 (d, J=2.3, 1H)

Step 2: Preparation of tert-butyl(5-amino-3-methoxypyridin-2-yl)methylcarbamate

A mixture of 10% Pd/C (530 mg) and tert-butyl3-methoxy-5-nitropyridin-2-yl(methyl)carbamate (5.30 g, 18.7 mmol) in4:1 MeOH/DCM (175 mL) was stirred at rt under and atmosphere of hydrogen2.5 h. After filtration through celite and washing with 15:85 MeOH/DCM(200 mL) the filtrate was combined with 4.55 g of a previously preparedbatch of crude product. The mixture was concentrated in vacuo andpurified by column chromatography eluting with 100% EtOAc to yield thetitle compound (9.13 g, 36.0 mmol) as a pale brown solid.

¹H NMR: (400 MHz, CDCl₃) δ: 1.37 (br. s, 9H), 3.14 (s, 3H), 3.70 (br. s,2H), 3.78 (s, 3H), 6.54 (d, J=2.3, 1H), 7.50 (d, J=2.3, 1H)

tert-Butyl(5-{[(2-chloropyridin-3-yl)sulfonyl]amino}-3-methoxypyridin-2-yl)methylcarbamate(IntC17)

The title compound (2.21 g, 5.15 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-3-methoxypyridin-2-yl)methylcarbamate (IntC16) (1.45 g, 5.72mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using themethods of (IntC1).

LCMS (Method B): m/z 427, 429 (M−H)− (ES−), 429, 431 (M+H)+ (ES+), at0.10 and 1.43 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 1.25 (m, 9H), 2.93 (s, 3H), 3.72 (s, 3H),7.12 (d, J=1.8, 1H), 7.59 (dd, J=7.8, 4.6, 1H), 7.66 (d, J=2.3, 1H),8.48 (dd, J=7.8, 1.8, 1H), 8.59 (dd, J=5.0, 1.8, 1H), 11.16 (br. s, 1H)

Route 5 4-Chloro-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide (IntD1)

A solution of 4-hydroxypyridine-3-sulfonic acid (5.0 g, 28.5 mmol),N,N-diisopropylethylamine (9.2 g, 71.3 mmol), phosphorus(V) oxychloride(10.9 g, 71.3 mmol) in 1,2-dichloroethane (50 mL) was heated at 90° C.for 45 min with TLC monitoring (hexane:EtOAc, 1:1). After cooling, thesolution was added to 3,4-dimethoxyaniline (4.8 g, 31.0 mmol),N,N-diisopropylethylamine (7.35 g, 57.0 mmol) in 1,2-dichloroethane (50mL) at −10° C. and the resulting mixture stirred for approximately 2 hat rt with TLC monitoring (hexane:EtOAc, 1:1). The mixture was thenadded to saturated aqueous NaHCO₃ (200 mL), extracted with DCM (3×50 mL)and the combined organic layers dried over Na₂SO₄ and concentrated invacuo. Purification by gradient column chromatography eluting with 0-20%EtOAc in hexane yielded the title compound (2.2 g, 6.69 mmol).

Mass spectroscopy: (ESI+ve) 329.2, 331.2 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ 3.65 (s, 3H), 3.65 (s, 3H), 6.60 (dd, J=8.5,2.4, 1H), 6.72 (d, J=2.4, 1H), 6.81 (d, J=8.9, 1H), 7.78 (d, J=5.2, 1H),8.72 (d, J=5.2, 1H), 8.96 (s, 1H), 10.52 (br s, 1H)

Route 6 4-(2-Chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntE1)

Step 1: Preparation of N-(2-chloro-6-fluorobenzyl)aniline

A mixture of aniline (3.95 mL, 43.3 mmol), 2-fluoro-6-chlorobenzaldehyde(7.46 g, 47.7 mmol) and glacial acetic acid (6.2 mL, 105.2 mmol) indichloroethane (100 mL) was heated at 70° C. for 2 h. After cooling tort, sodium triacetoxyborohydride (13.8 g, 65.1 mmol) was added and themixture stirred at rt for 2.5 h, before further sodiumtriacetoxyborohydride (4.6 g, 21.7 mmol) was added and the mixturestirred at rt for 1 h. H₂O (100 mL) was added cautiously and the mixturewas stirred for 5 min; 10M aqueous NaOH (20 mL) and DCM (50 mL) wereadded, the phases were separated, and the aqueous phase was extractedwith DCM (2×50 mL). The combined organic phases were washed with brine(50 mL) and concentrated in vacuo. Purification by gradient columnchromatography eluting with 0-10% EtOAc in iso-hexane yielded the titlecompound (10.5 g, 44.6 mmol).

LCMS (Method B): m/z 235.0, 237.0 (M+H)+ (ES+), 85%

¹H NMR: (400 MHz, DMSO) δ 4.33 (d, J=5.5, 2H), 5.77 (br s, 1H), 6.56 (t,J=7.3, 1H), 6.69 (d, J=8.0, 2H), 7.09 (t, J=7.9, 2H), 7.20-7.30 (m, 1H),7.32-7.45 (m, 2H)

Step 2: Preparation of4-(2-chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntE1)

A solution of chlorosulfonylisocyanate (5.04 mL, 57.9 mmol) innitroethane (100 mL) was cooled to approximately −40° C. and a solutionof N-(2-chloro-6-fluorobenzyl)aniline (10.5 g, 44.6 mmol) in nitroethane(80 mL) added dropwise over approximately 10 min. The mixture wasstirred at −40° C. for 10 min, then rt for 1 h, before the addition offurther chlorosulfonylisocyanate (1.94 mL, 22.3 mmol) and stirring for30 min at rt. Aluminium chloride (8.32 g, 62.4 mmol) was added and themixture heated at reflux for 30 min, before cooling to rt and cautiousaddition to stirred ice-H₂O (approximately 300 mL). After stirring for15 min, the title compound (11.8 g, 34.6 mmol) was isolated byfiltration.

LCMS (Method B): m/z 339.3, 341.3 (M−H)− (ES−), 100%

¹H NMR: (400 MHz, DMSO) δ 5.42 (s, 2H), 7.12-7.24 (m, 1H), 7.28-7.42 (m,3H), 7.47 (d, J=8.5, 1H), 7.66-7.74 (m, 1H), 7.83 (d, J=7.8, 1H)

4-(4-Chloro-2-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntE2)

The title compound (4.2 g, 12.3 mmol) was prepared in two steps fromaniline (8.8 g, 94.7 mmol), 2-fluoro-4-chlorobenzaldehyde (9.0 g, 63.0mmol), glacial acetic acid (11.36 g, 183 mmol) and sodiumtriacetoxyborohydride (20.0 g, 94.5 mmol); followed bychlorosulfonylisocyanate (4.3 g, 30.0 mmol) and aluminium chloride (4.78g, 35.7 mmol) using the methods of (IntE1).

Mass spectroscopy: m/z 341.3, 343.3 (M+H)+ (ES+)

¹H NMR: (400 MHz, DMSO) δ 5.31 (s, 2H), 6.98-7.14 (m, 1H), 7.23 (dd,J=8.2, 1.5, 1H), 7.31-7.40 (m, 2H), 7.50 (dd, J=10.2, 2.0, 1H),7.61-7.71 (m, 1H), 7.83-7.92 (m, 1H)

4-(2,6-Difluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntE3)

Step 1: Preparation of N-(2,6-difluorobenzyl)aniline

A mixture of aniline (2.26 g, 24.3 mmol), 2,6-difluorobenzaldehyde (3.79g, 26.7 mmol) and glacial acetic acid (3.5 mL, 60.8 mmol) indichloroethane (50 mL) was heated at 70° C. for 2 h. After cooling tort, sodium triacetoxyborohydride (5.67 g, 26.8 mmol) was added and themixture heated at 70° C. for 1.5 h, before cooling to rt, further sodiumtriacetoxyborohydride (5.67 g, 26.8 mmol) was added and the mixture washeated at 70° C. for a further 75 min before cooling to rt. H₂O (50 mL),DCM (25 mL) and 1M aqueous NaOH (100 mL) were added and the phases wereseparated.

The aqueous phase was extracted with DCM (2×50 mL) and the combinedorganic phases were extracted with DCM (2×50 mL), washed with brine (50mL) and concentrated in vacuo. Purification by gradient columnchromatography eluting with 0-20% EtOAc in heptane yielded the titlecompound (2.88 g, 13.1 mmol).

LCMS (Method B): m/z 220 (M+H)⁺ (ES+), at 4.38 min, 95%.

¹H NMR: (400 MHz, DMSO) δ 4.26 (d, J=5.8, 2H), 5.96 (t, J=5.8, 1H), 6.54(t, J=7.3, 1H), 6.66 (d, J=7.8, 2H), 7.02-7.16 (m, 4H), 7.34-7.45 (m,1H)

Step 2: 4-(2,6-difluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntE3)

A solution of chlorosulfonylisocyanate (0.29 mL, 3.33 mmol) innitroethane (5 mL) was cooled to approximately −40° C. and a solution ofN-(2,6-difluorobenzyl)aniline (562 mg, 2.56 mmol) in nitroethane (3 mL)was added dropwise over approximately 10 min. The mixture was stirred at−40° C. for approximately 10 min, then at 0° for 15 min. Aluminiumchloride (479 mg, 3.59 mmol) was then added and the mixture heated atreflux for 30 min before cooling to rt. Separately, the process wasrepeated using chlorosulfonylisocyanate (1.20 mL, 13.8 mmol) innitroethane (20 mL), N-(2,6-difluorobenzyl)aniline (2.32 g, 10.6 mmol)in nitroethane (15 mL), followed by aluminium chloride (1.97 g, 14.8mmol). The two reaction mixtures were combined and cautiously added tostirred ice-H₂O (approximately 100 mL) and the title compound (3.04 g,9.37 mmol) was isolated by filtration.

LCMS (Method B): m/z 323 (M−H)⁻ (ES−), at 1.35 min, >95%

¹H NMR: (400 MHz, DMSO) δ 5.41 (s, 2H), 7.02-7.13 (m, 2H), 7.30-7.43 (m,2H), 7.52 (d, J=8.3, 1H), 7.68-7.76 (m, 1H), 7.83 (dd, J=7.8, 1.5, 1H)

4-(2,4,6-Trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntE4)

Step 1: Preparation of N-(2,4,6-trifluorobenzyl)aniline

A mixture of aniline (3.80 mL, 41.7 mmol), 2,4,6-trifluorobenzaldehyde(7.35 g, 45.9 mmol) and glacial acetic acid (6.0 mL, 104.4 mmol) indichloroethane (100 mL) was heated at 70° C. for 2.5 h. After cooling tort, sodium triacetoxyborohydride (17.7 g, 83.5 mmol) was added and themixture stirred at rt for 1.5 h, before the cautious addition of H₂O(100 mL), followed by 10M aqueous NaOH (30 mL) and DCM (50 mL). Thephases were separated, and the aqueous phase was extracted with DCM(2×100 mL), the combined organic phases were washed with brine (50 mL)and concentrated in vacuo. Purification by gradient columnchromatography eluting with 0-6% EtOAc in iso-hexane yielded the titlecompound (9.90 g, 41.7 mmol).

LCMS (Method B): m/z 238 (M+H)+ (ES+), at 4.33 min, 90%

¹H NMR: (400 MHz, DMSO) δ 4.21 (d, J=5.8, 2H), 5.96 (t, J=5.8, 1H), 6.55(t, J=7.3, 1H), 6.64 (d, J=7.8, 2H), 7.04-7.12 (m, 2H), 7.17-7.27 (m,2H)

Step 2: Preparation of4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide(IntE4)

A solution of chlorosulfonylisocyanate (4.72 mL, 54.2 mmol) innitroethane (75 mL) was cooled to approximately −40° C. and a solutionof N-(2,4,6-trifluorobenzyl)aniline (9.90 g, 41.7 mmol) in nitroethane(75 mL) added dropwise over approximately 10 min. The mixture wasstirred at −40° C. for 10 min, then at 0° C. for 30 min. Aluminiumchloride (5.56 g, 41.7 mmol) was added and the mixture heated at refluxfor 30 min, before cooling to rt and cautious addition to stirredice-H₂O (approximately 250 mL). The title compound (6.12 g, 17.9 mmol)was isolated by filtration.

LCMS (Method B): m/z 341.1 (M−H)− (ES−), at 1.17 min, 95%

¹H NMR: (400 MHz, DMSO) δ 5.37 (s, 2H), 7.14-7.24 (m, 2H), 7.36 (t,J=7.7, 1H), 7.53 (d, J=8.5, 1H), 7.71-7.78 (m, 1H), 7.84 (dd, J=7.8,1.3, 1H)

5-(Bromomethyl)-1,3-dimethyl-1H-pyrazole (IntE5)

CBr₄ (4.7 g, 14.2 mmol) was added to a solution of(1,3-dimethyl-1H-pyrazol-5-yl)methanol (1.2 g, 9.5 mmol) andtriphenylphosphine (3.7 g, 14.2 mmol) in THF (20 mL) at 0° C. and theresulting mixture was stirred for approximately 2 h at rt. Afterconcentration in vacuo purification by column chromatography elutingwith 2% EtOAc in hexane yielded the title compound (1.31 g, 6.93 mmol).

TLC: Rf=0.85 (EtOAc:hexane, 3:8)

Mass spectroscopy: (ESI+ve) 189.9 [M+H]⁺

Route 72-(5,6-Dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF1)

Step 1: Preparation of2-chloro-N-(5,6-dimethylpyridin-2-yl)pyridine-3-sulfonamide

The title compound (5.0 g, 16.8 mmol) was prepared from2-chloropyridine-3-sulfonyl chloride (5.0 g, 23.7 mmol) and5,6-dimethylpyridin-2-amine (2.4 g, 19.6 mmol) in pyridine (25 mL) at rtusing the methods of (IntC1), step 1.

Mass spectroscopy: (ESI+ve) 298.0 [M+H]+

Step 2: Preparation of2-amino-N-(5,6-dimethylpyridin-2-yl)pyridine-3-sulfonamide

A solution of2-chloro-N-(5,6-dimethylpyridin-2-yl)pyridine-3-sulfonamide (2.0 g, 6.7mmol) in THF (30 mL) was cooled to −50° C. NH₃(g) was purged into anautoclave and the mixture heated at 140° C. for 16 h. After filtrationand concentration in vacuo purification by gradient flash chromatographyeluting with 80-90% EtOAc in hexane yielded the title compound (0.6 g,2.16 mmol).

Mass spectroscopy: (ESI+ve) 279.1 [M+H]+

Step 3: Preparation of2-(5,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide

The title compound (0.4 g, 1.31 mmol) was prepared from2-amino-N-(5,6-dimethylpyridin-2-yl)pyridine-3-sulfonamide (0.6 g, 2.16mmol) and triphosgene (0.7 g, 2.36 mmol) in 1,4-dioxane (15 mL) at 80°C. using the methods of (IntA1), step 3.

LCMS (Method B): m/z 305.0 (M+H)+ (ES+), at 0.10 and 0.98 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.32 (s, 3H), 2.45 (s, 3H), 7.29 (d, J=7.9,1H), 7.40-7.45 (m, 1H), 7.74 (d, J=7.9, 1H), 8.37-8.41 (m, 1H), 8.74(dd, J=4.9, 1.5, 1H), 12.24 (s, 1H)

2-(4,6-Dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF2)

The title compound (0.6 g, 1.97 mmol) was prepared in three steps from2-chloropyridine-3-sulfonyl chloride (6.5 g, 30.0 mmol) and4,6-dimethylpyridin-2-amine (2.5 g, 20.4 mmol) in pyridine (6 mL) at rt;followed by ammonia in an autoclave at 140° C. for 16 h; followed bytriphosgene (930 mg, 3.14 mmol) in 1,4-dioxane (20 mL) at approximately90° C. for 6 h using the methods of (IntF1).

LCMS (Method B): m/z 305.0 (M+H)+ (ES+), at 0.11 and 0.85 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.35 (s, 3H), 2.45 (s, 3H), 7.18-7.25 (m,1H), 7.27 (s, 1H), 7.43 (dd, J=7.9, 4.9, 1H), 8.39 (dd, J=7.8, 1.7, 1H),8.74 (dd, J=4.9, 1.8, 1H), 12.26 (s, 1H)

2-(2,6-Dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF3)

The title compound (2.6 g, 7.73 mmol) was prepared in three steps from2-chloropyridine-3-sulfonyl chloride (8.24 g, 38.9 mmol) and2,6-dimethoxypyridin-4-amine (6.0 g, 38.9 mmol) in pyridine (25 mL) atrt; followed by ammonia in an autoclave at 100° C. for 16 h; followed by1,1′-carbonyldiimidazole (6.2 g, 38.2 mmol) in 1,2-dichloroethane (100mL) at 90° C. for 16 h using the methods of (IntF1), steps 1 and 2, and(IntA14), step 3.

LCMS (Method B): m/z 337.1 (M+H)+ (ES+), at 0.10 and 1.33 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.91 (s, 6H), 6.51 (s, 2H), 7.42-7.45 (m,1H), 8.44 (dd, J=7.8, 1.8, 1H), 8.75 (dd, J=4.8, 1.8, 1H), 12.33 (br. s,1H)

2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF4)

Steps 1 and 2: Preparation of2-amino-N-(5,6-dimethoxypyridin-3-yl)pyridine-3-sulfonamide

2-chloro-N-(5,6-dimethoxypyridin-3-yl)pyridine-3-sulfonamide (20.0 g,60.7 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (13.7g, 64.9 mmol) and 5,6-dimethoxypyridin-3-amine (10 g, 64.9 mmol) inpyridine (50 mL) at rt using the methods of (IntC1), step 1.2-Chloro-N-(5,6-dimethoxypyridin-2-yl) pyridine-3-sulfonamide (3.0 g,9.09 mmol) was dissolved in THF (20 mL) and NH₃(g) bubbled through thereaction mixture at −40° C. for 15 min. The reaction mixture was stirredfor 1 d at rt before concentration in vacuo. Purification by columnchromatography eluting with 50-60% EtOAc in hexane yielded the titlecompound (2.0 g, 6.44 mmol) as a white solid.

Mass spectroscopy: (ESI+ve) 311.2 [M+H]+

Step 3: Preparation of2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide

The title compound (1.4 g, 4.16 mmol) was prepared from2-amino-N-(5,6-dimethoxypyridin-3-yl)pyridine-3-sulfonamide (2.0 g, 6.44mmol) and 1,1′-carbonyldiimidazole (3.13 g, 19.3 mmol) in1,2-dichloroethane (15 mL) at 90° C. for 16 h using the methods of(IntA14) step 3.

LCMS (Method B): m/z 337.0 (M+H)+ (ES+), at 0.10 and 1.02 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.78 (s, 3H), 3.94 (s, 3H), 7.41-7.46 (m,2H), 7.80 (d, J=2.0, 1H), 8.46 (dd, J=7.9, 1.6, 1H), 8.75 (dd, J=4.8,1.8, 1H), 12.28 (s, 1H)

SYNTHESIS OF EXAMPLES Route 1 Typical Mitsonobu coupling procedure forthe preparation of examples from route 1, as exemplified by thepreparation of4-(2,6-Dimethylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (77)

A mixture of (IntA1) (0.2 g, 0.59 mmol), triphenylphospine (0.17 g, 0.65mmol) and 2,6-dimethylbenzyl alcohol (0.08 g, 0.59 mmol) was dissolvedin THF (3.0 mL) in a sealed tube and sonicated for 5 min. Diisopropylazodicarboxylate (0.13 g, 0.65 mmol) was added and reaction wassonicated for another 2 h. H₂O (10 mL) was added and the mixture wasextracted with EtOAc (3×25 mL). The combined organic layers were washedwith H₂O (2×10 mL) and brine and dried over Na₂SO₄ followed byconcentration in vacuo. Purification by gradient flash chromatography,eluting with 10-15% EtOAc yielded the title compound (0.05 g, 0.11mmol).

LCMS (Method B): m/z 453.2 (M+H)+ (ES+), at 4.80 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.32 (s, 6H), 3.70 (s, 3H), 3.80 (s, 3H),5.29 (s, 2H), 6.79-6.88 (m, 2H), 6.94-7.11 (m, 4H), 7.44 (t, J=7.6, 1H),7.69 (d, J=8.5, 1H), 7.78-7.88 (m, 1H), 7.95 (d, J=7.6, 1H)

4-(2-Fluoro-6-methylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (79)

The title compound (0.05 g, 0.11 mmol) was prepared from (IntA1) (0.2 g,0.59 mmol) and 2-fluoro-6-methylbenzylalcohol (0.08 g, 0.59 mmol) usingthe methods of (77).

LCMS (Method B): m/z 457.2 (M+H)+ (ES+), at 4.60 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.33 (s, 3H), 3.70 (s, 3H), 3.79 (s, 3H),5.39 (br s, 2H), 6.83 (br s, 1H), 6.90 (d, J=7.6, 1H), 6.94-7.14 (m,3H), 7.21 (d, J=6.1, 1H), 7.42 (t, J=7.3, 1H), 7.66 (d, J=8.2, 1H), 7.81(br s, 1H), 7.91 (d, J=7.0, 1H)

2-(3,4-Dimethoxyphenyl)-4-[(2,4-dimethylpyridin-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (84)

The title compound (0.03 g, 0.07 mmol) was prepared from (IntA1) (0.15g, 0.44 mmol) and 2,4-dimethyl-3-pyridinemethanol (0.07 g, 0.49 mmol)using the methods of (77).

LCMS (Method B): m/z 454.2 (M+H)+ (ES+), at 3.50 min, 100%

¹H NMR: (400 MHz, CDCl₃) δ: 2.62 (s, 3H), 2.92 (s, 3H), 3.86 (s, 3H),3.91 (s, 3H), 5.25 (s, 2H), 6.72 (d, J=2.1, 1H), 6.80-6.87 (m, 1H),6.88-6.95 (m, 1H), 7.44-7.61 (m, 3H), 7.87 (t, J=7.3, 1H), 8.04 (dd,J=7.8, 1.1, 1H), 8.67 (d, J=5.5, 1H)

4-[(5-Bromo-3-fluoropyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (89)

The title compound (0.08 g, 0.15 mmol) was prepared from (IntA1) (0.2 g,0.59 mmol) and 5-bromo-3-fluoro-2-pyridinemethanol (0.13 g, 0.65 mmol)using the methods of (77).

LCMS (Method B): m/z 522.1, 524.0 (M+H)+ (ES+), at 4.36 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.73 (s, 3H), 3.81 (s, 3H), 5.46 (br s, 2H),6.86 (br s, 1H), 6.94 (d, J=8.2, 1H), 7.08 (d, J=8.5, 1H), 7.39-7.50 (m,1H), 7.54 (d, J=8.2, 1H), 7.78 (t, J=7.5, 1H), 7.99 (d, J=7.6, 1H), 8.26(d, J=9.5, 1H), 8.48 (s, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(3,4,5-trimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (78)

The title compound (0.05 g, 0.10 mmol) was prepared from (IntA2) (0.2 g,0.54 mmol) and 2-chloro-6-fluorobenzyl alcohol (0.09 g, 0.60 mmol) usingthe methods of (77).

LCMS (Method B): m/z 507.2, 509.2 (M+H)+ (ES+), at 4.92 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.77 (s, 6H), 5.36 (s, 2H),6.80 (s, 2H), 7.19 (td, J=8.5, 2.1, 1H), 7.24-7.33 (m, 1H), 7.38 (d,J=8.5, 1H), 7.47 (t, J=7.6, 1H), 7.57 (dd, J=8.5, 2.1, 1H), 7.79 (t,J=7.9, 1H), 8.02 (d, J=7.6, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(6-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (142)

The title compound (0.03 g, 0.07 mmol) was prepared from (IntA3) (0.2 g,0.69 mmol) and 2-chloro-6-fluorobenzyl alcohol (0.12 g, 0.76 mmol) usingthe methods of (77).

LCMS (Method B): m/z 432.1, 434.1 (M+H)+ (ES+), at 4.16 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.55 (s, 3H), 5.52 (s, 2H), 7.17-7.30 (m,1H), 7.31-7.53 (m, 4H), 7.67-7.79 (m, 2H), 7.87 (t, J=7.6, 1H), 7.98 (d,J=7.3, 1H), 8.39 (d, J=2.1, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (143)

The title compound (0.11 g, 0.25 mmol) was prepared from (IntA4) (0.18g, 0.59 mmol) and 2-chloro-6-fluorobenzyl alcohol (0.14 g, 0.88 mmol)using the methods of (77).

LCMS (Method B): m/z 448.1, 450.2 (M+H)+ (ES+), at 4.59 min, >95%

¹H NMR: (400 MHz, DMSO) S: 3.91 (s, 3H), 5.50 (s, 2H), 6.85 (d, J=1.2,1H), 7.03 (dd, J=5.5, 1.5, 1H), 7.17-7.29 (m, 1H), 7.30-7.52 (m, 3H),7.74 (d, J=8.2, 1H), 7.82-7.93 (m, 1H), 7.93-8.02 (m, 1H), 8.33 (d,J=5.5, 1H)

2-(6-Methoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (144)

The title compound (0.05 g, 0.11 mmol) was prepared from (IntA5) (0.2 g,0.65 mmol) and 2,4,6-trifluorobenzyl alcohol (0.11 g, 0.72 mmol) usingthe methods of (77).

LCMS (Method B): m/z 450.2 (M+H)+ (ES+), at 4.54 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 3.81 (s, 3H), 5.46 (s, 2H), 7.00 (d, J=8.2,1H), 7.06 (d, J=7.3, 1H), 7.22 (t, J=8.7, 2H), 7.47 (t, J=7.6, 1H), 7.78(d, J=8.5, 1H), 7.83-7.97 (m, 3H)

4-(2-Chloro-4-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (80)

The title compound (0.16 g, 0.34 mmol) was prepared from (IntA6) (0.30g, 0.90 mmol) and 2-chloro-4-fluorobenzyl alcohol (0.21 g, 1.35 mmol)using the methods of (77).

LCMS (Method B): m/z 475.2, 477.0 (M+H)+ (ES+), at 5.53 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 2.26 (s, 6H), 3.71 (s, 3H), 5.35 (s, 2H),7.09-7.29 (m, 4H), 7.34-7.51 (m, 2H), 7.56 (dd, J=8.7, 2.0, 1H), 7.79(t, J=7.8, 1H), 8.00 (d, J=7.6, 1H)

2-(1,3-Benzothiazol-6-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (124)

The title compound (0.05 g, 0.11 mmol) was prepared from (IntA7) (0.2 g,0.60 mmol) and 2,4,6-trifluorobenzyl alcohol (0.1 g, 0.60 mmol)) usingthe methods of (77).

LCMS (Method B): m/z 476.1 (M+H)+ (ES+), at 4.36 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 5.48 (br s, 2H), 7.23 (t, J=8.7, 2H),7.43-7.54 (m, 2H), 7.78 (d, J=8.5, 1H), 7.90 (t, J=7.6, 1H), 7.98 (d,J=7.6, 1H), 8.22 (d, J=8.5, 1H), 8.30 (s, 1H), 9.55 (s, 1H)

2-[6-(Dimethylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (158)

The title compound (0.08 g, 0.17 mmol) was prepared from (IntA17) (0.18g, 0.58 mmol) and 2,4,6-trifluorobenzyl alcohol (0.10 g, 0.63 mmol)using the methods of (77).

LCMS (Method B): m/z 463.2 (M+H)+ (ES+), at 4.74 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.99 (s, 6H), 5.44 (s, 2H), 6.54 (d, J=7.3,1H), 6.72 (d, J=8.5, 1H), 7.21 (t, J=8.9, 2H), 7.44 (t, J=7.6, 1H), 7.64(t, J=7.9, 1H), 7.74 (d, J=8.5, 1H), 7.81-7.96 (m, 2H)

2-[2-(Dimethylamino)pyridin-4-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (159)

The title compound (0.07 g, 0.15 mmol) was prepared from (IntA18) (0.07g, 0.22 mmol) and 2,4,6-trifluorobenzyl alcohol (0.04 g, 0.24 mmol)using the methods of (77).

LCMS (Method B): m/z 463.2 (M+H)+ (ES+), at 4.43 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.02 (s, 6H), 5.45 (s, 2H), 6.55 (d, J=1.8,2H), 7.22 (t, J=8.7, 2H), 7.46 (t, J=7.6, 1H), 7.75 (d, J=8.5, 1H),7.83-7.91 (m, 1H), 7.95 (d, J=7.6, 1H), 8.16-8.24 (m, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (127)

The title compound (90 mg, 0.20 mmol) was prepared from (IntA13) (0.3 g,0.98 mmol) and 2-chloro-6-fluorobenzyl alcohol (45 mg, 0.28 mmol) usingthe methods of (77).

LCMS (Method B): m/z 449.2, 451.2 (M+H)+ (ES+), at 4.20 min, >95%

¹H NMR: (400 MHz, CDCl₃) δ: 2.21 (s, 3H), 3.88 (s, 3H), 5.09 (s, 2H),5.51 (s, 2H), 6.15 (s, 1H), 6.93-7.04 (m, 1H), 7.15-7.34 (m, 3H), 7.39(d, J=8.5, 1H), 7.55-7.68 (m, 1H), 7.88 (dd, J=7.8, 1.1, 1H)

4-(2-Chloro-6-fluoro-4-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (113)

A solution of diisopropyl azodicarboxylate (56 mg, 0.28 mmol) in THF (1mL) was added to a solution of (IntA1) (84 mg, 0.25 mmol), (IntA25) (52mg, 0.28 mmol) and triphenylphosphine (72 mg, 0.28 mmol) in THF (0.5 mL)and the mixture was stirred at rt for 2 d. After concentration in vacuo,purification by gradient flash chromatography, eluting with 12-100%EtOAc in iso-hexane yielded the title compound (63 mg, 0.12 mmol).

LCMS (Method B): m/z 507 (M+H)⁺ (ES⁺), at 4.59 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.77 (s, 3H), 3.82 (s, 3H),5.43 (s, 2H), 6.86-6.96 (m, 4H), 7.08 (d, J=8.8, 1H), 7.43 (t, J=7.7,1H), 7.68 (d, J=8.3, 1H), 7.78-7.88 (m, 1H), 7.93 (dd, J=7.8, 1.3, 1H)

4-[(3,5-Difluoropyridin-4-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (85)

The title compound (47 mg, 0.10 mmol) was prepared from (IntA1) (167 mg,0.50 mmol) and 3,5-difluoropyridine-4-methanol (109 mg, 0.75 mmol) usingthe methods of (113).

LCMS (Method B): m/z 462 (M+H)+ (ES+), at 3.62 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.82 (s, 3H), 5.56 (s, 2H),6.87 (d, J=2.3, 1H), 6.92 (dd, J=8.5, 2.3, 1H), 7.08 (d, J=8.5, 1H),7.48 (t, J=7.5, 1H), 7.72 (d, J=8.5, 1H), 7.87 (t, J=7.3, 1H), 7.98 (d,J=8.0, 1H), 8.53 (s, 2H)

2-(3,4-Dimethoxyphenyl)-4-[(3-fluoropyridin-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (88)

The title compound (152 mg, 0.34 mmol) was prepared from (IntA1) (167mg, 0.50 mmol), and (3-fluoropyridin-2-yl)methanol (95 mg, 0.75 mmol)using the methods of (113).

LCMS (Method B): m/z 444 (M+H)+ (ES+), at 3.72 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.73 (s, 3H), 3.81 (s, 3H), 5.51 (s, 2H),6.87 (d, J=2.3, 1H), 6.95 (dd, J=8.5, 2.3, 1H), 7.08 (d, J=8.8, 1H),7.40-7.46 (m, 2H), 7.53 (d, J=8.5, 1H), 7.75-7.80 (m, 2H), 7.99 (d,J=8.0, 1H), 8.31 (d, J=4.8, 1H)

4-[(3,5-Dichloropyridin-4-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (90)

The title compound (217 mg, 0.44 mmol) was prepared from (IntA1) (167mg, 0.50 mmol), and 3,5-dichloro-4-hydroxymethylpyridine (133 mg, 0.75mmol) using the methods of (113).

LCMS (Method B): m/z 494/496 (M+H)+ (ES+), at 3.80 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.71 (s, 3H), 3.80 (s, 3H), 5.53 (s, 2H),6.85-6.90 (m, 2H), 7.05 (d, J=8.8, 1H), 7.48 (t, J=7.5, 1H), 7.72 (d,J=8.5, 1H), 7.87 (t, J=7.3, 1H), 7.99 (d, J=7.8, 1H), 8.63 (s, 2H)

4-(2-Chloro-4,6-difluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (110)

The title compound (163 mg, 0.34 mmol) was prepared from (IntA12) (160mg, 0.5 mmol) and (IntA22) (134 mg, 0.75 mmol) using the methods of(113).

LCMS (Method B): m/z 481 (M+H)+ (ES+), at 5.00 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.49 (s, 3H), 5.46 (s, 2H), 7.13 (d, J=7.5,1H), 7.18 (s, 1H), 7.31-7.39 (m, 1H), 7.40-7.50 (m, 4H), 7.73 (d, J=8.3,1H), 7.87 (t, J=7.3, 1H), 7.96 (d, J=7.8, 1H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(6-methoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (139)

The title compound (162 mg, 0.35 mmol) was prepared from (IntA5) (152mg, 0.5 mmol), and (2-chloro-4,6-difluorophenyl)methanol ((IntA22), 134mg, 0.75 mmol) using the methods of (113).

LCMS (Method B): m/z 466 (M+H)+ (ES+), at 4.72 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.81 (s, 3H), 5.46 (s, 2H), 6.99 (d, J=8.3,1H), 7.05 (d, J=7.3, 1H), 7.35 (t, J=9.0, 1H), 7.41 (d, J=8.3, 1H), 7.47(t, J=7.5, 1H), 7.77 (d, J=8.5, 1H), 7.85-7.95 (m, 3H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (141)

The title compound (130 mg, 0.28 mmol) was prepared from (IntA4) (152mg, 0.5 mmol), and (2-chloro-4,6-difluorophenyl)methanol ((IntA22), 134mg, 0.75 mmol) using the methods of (113).

LCMS (Method B): m/z 466/468 (M+H)+ (ES+), at 4.68 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.91 (s, 3H), 5.45 (s, 2H), 6.84 (d, J=1.5,1H), 7.02 (dd, J=5.5, 1.7, 1H), 7.36 (t, J=9.0, 1H), 7.42 (d, J=8.5,1H), 7.47 (t, J=7.5, 1H), 7.76 (d, J=8.5, 1H), 7.89 (t, J=7.3, 1H), 7.79(d, J=7.8, 1H), 8.32 (d, J=5.5, 1H)

4-[(3-Methylpyridin-2-yl)methyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (87)

The title compound (11 mg, 0.03 mmol) was prepared from (IntA12) (48 mg,0.15 mmol), and (3-methylpyridin-2-yl)methanol (28 mg, 0.23 mmol) usingthe methods of (113).

LCMS (Method B): m/z 426 (M+H)+ (ES+), at 4.46 min, 98%

¹H NMR: (400 MHz, DMSO) δ: 2.40 (s, 3H), 2.50 (s, 3H), 5.40 (s, 2H),7.12-7.25 (m, 3H), 7.32 (d, J=8.5, 1H), 7.39-7.53 (m, 3H), 7.64 (d,J=7.0, 1H), 7.70-7.78 (m, 1H), 7.99 (dd, J=7.9, 1.4, 1H), 8.25 (d,J=3.8, 1H)

4-(Cyclohexylmethyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (62)

The title compound (38 mg, 0.09 mmol) was prepared from (IntA12) (48 mg,0.15 mmol), and cyclohexylmethanol (19 mg, 0.17 mmol) using the methodsof (113).

LCMS (Method B): m/z 417 (M+H)+ (ES+), at 5.22 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 0.90-1.05 (m, 2H), 1.06-1.18 (m, 3H),1.54-1.75 (m, 6H), 2.49 (s, 3H), 4.11 (d, J=7.0, 2H), 7.18 (d, J=7.8,1H), 7.21 (s, 1H), 7.39-7.50 (m, 3H), 7.80-7.90 (m, 2H), 7.96 (d, J=7.8,1H)

4-(2,4-Difluoro-6-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (104)

The title compound (212 mg, 0.43 mmol) was prepared from (IntA1) (179mg, 0.54 mmol), and (IntA23) (140 mg, 0.80 mmol) using the methods of(113).

LCMS (Method B): m/z 491 (M+H)+ (ES+), at 4.46 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 3.73 (s, 3H), 3.79 (s, 3H), 3.83 (s, 3H),5.37 (s, 2H), 6.76-6.92 (m, 3H), 6.96 (dd, J=8.5, 2.5, 1H), 7.10 (d,J=8.5, 1H), 7.39 (t, J=7.7, 1H), 7.65 (d, J=8.5, 1H), 7.75-7.85 (m, 1H),7.89 (dd, J=7.9, 1.1, 1H)

4-(2-Chloro-6-fluoro-4-methylbenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (106)

The title compound (199 mg, 0.41 mmol) was prepared from (IntA1) (149mg, 0.44 mmol), and (IntA24) (116 mg, 0.66 mmol) using the methods of(113).

LCMS (Method B): m/z 491, 493 (M+H)+ (ES+), at 4.79 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.28 (s, 3H), 3.72 (s, 3H), 3.82 (s, 3H),5.46 (s, 2H), 6.87 (d, J=2.3, 1H), 6.93 (dd, J=8.5, 2.5, 1H), 7.06-7.09(m, 2H), 7.19 (br. s, 1H), 7.42 (t, J=7.7, 1H), 7.67 (d, J=8.5, 1H),7.83 (td, J=7.9, 1.3, 1H), 7.94 (dd, J=7.8, 1.3, 1H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (107)

The title compound (176 mg, 0.36 mmol) was prepared from (IntA1) (148mg, 0.44 mmol), and (IntA22) (118 mg, 0.66 mmol) using the methods of(113).

LCMS (Method B): m/z 495, 497 (M+H)+ (ES+), at 4.59 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.82 (s, 3H), 5.46 (s, 2H),6.86 (d, J=2.3, 1H), 6.91 (dd, J=8.5, 2.3, 1H), 7.70 (d, J=8.5, 1H),7.33-7.47 (m, 3H), 7.71 (d, 8.5, 1H), 7.85 (td, J=8.7, 1.4, 1H), 7.95(dd, J=7.9, 1.4, 1H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (157)

The title compound (11 mg, 0.02 mmol) was prepared from (IntA21) (84 mg,0.25 mmol) and (IntA22) (49 mg, 0.28 mmol) using the methods of (113).

LCMS (Method B): m/z 496/498 (M+H)+ (ES+), at 5.20 min, 100%

¹H NMR: (400 MHz, DMSO) δ: (400 MHz, DMSO) δ 3.90 (s, 6H), 5.44 (s, 2H),6.38 (s, 2H), 7.32-7.40 (m, 1H), 7.41-7.50 (m, 2H), 7.74 (d, J=8.5, 1H),7.83-7.92 (m, 1H), 7.96 (dd, J=8.0, 1.3, 1H)

4-(2-Chloro-6-fluoro-4-methylbenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (135)

The title compound (44 mg, 0.10 mmol) was prepared from (IntA15) (76 mg,0.25 mmol) and (IntA24) (48 mg, 0.28 mmol) using the methods of (113).

LCMS (Method B): m/z 462 (M+H)+ (ES+), at 4.99 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.28 (s, 3H), 3.92 (s, 3H), 5.47 (s, 2H),7.00 (d, J=8.8, 1H), 7.07 (d, J=11.0, 1H), 7.20 (s, 1H), 7.45 (t, J=7.7,1H), 7.66-7.76 (m, 2H), 7.81-7.90 (m, 1H), 7.97 (dd, J=7.8, 1.3, 1H),8.14 (d, J=2.5, 1H)

4-(2-Chloro-6-fluoro-4-methoxybenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (154)

The title compound (35 mg, 0.07 mmol) was prepared from (IntA15) (76 mg,0.25 mmol) and (IntA25) (52 mg, 0.28 mmol) using the methods of (113).

LCMS (Method B): m/z 478/480 (M+H)+ (ES+), at 4.70. min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.77 (s, 3H), 3.92 (s, 3H), 5.44 (s, 2H),6.89 (dd, J=12.4, 2.4, 1H), 6.96 (s, 1H), 7.00 (d, J=8.8, 1H), 7.45 (t,J=7.7, 1H), 7.64-7.76 (m, 2H), 7.80-7.91 (m, 1H), 7.97 (dd, J=7.8, 1.3,1H), 8.14 (d, J=2.5, 1H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (155

The title compound (28 mg, 0.06 mmol) was prepared from (IntA19) (84 mg,0.25 mmol) and (IntA22) (49 mg, 0.28 mmol) using the methods of (113).

LCMS (Method B): m/z 496/498 (M+H)+ (ES+), at 4.58 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.77 (s, 3H), 3.93 (s, 3H), 5.47 (s, 2H),7.26 (d, J=2.0, 1H), 7.37 (ddd, J=11.5, 9.3, 2.5, 1H), 7.41-7.52 (m,2H), 7.71 (d, J=2.3, 1H), 7.74 (d, J=8.3, 1H), 7.83-7.92 (m, 1H), 7.98(dd, J=7.9, 1.4, 1H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (161)

The title compound (29 mg, 0.06 mmol) was prepared from (IntA20) (84 mg,0.25 mmol) and (IntA22) (49 mg, 0.28 mmol) using the methods of (113).

LCMS (Method B): m/z 496/498 (M+H)+ (ES+), at 4.55 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.79 (s, 3H), 3.85 (s, 3H), 5.45 (s, 2H),7.01 (d, J=8.0, 1H), 7.30-7.39 (m, 1H), 7.40-7.50 (m, 3H), 7.74 (d,J=8.5, 1H), 7.81-7.90 (m, 1H), 7.93 (dd, J=7.8, 1.3, 1H)

2-(2,6-Dimethoxypyridin-4-yl)-4-[(5-fluoro-3-methylpyridin-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (162)

A solution of TMAD (1,1′-azobis(N,N-dimethylformamide)) (47 mg, 0.28mmol) in THF (0.5 mL) was added dropwise to a solution of (IntA21) (84mg, 0.25 mmol), triphenyl phosphine (72 mg, 0.28 mmol) and (IntA26) (39mg, 0.28 mmol) in THF (1 mL) and the reaction mixture stirred at rt for5 h. Further (IntA26) (10 mg, 0.07 mmol) was added and the reactionstirred for 50 h at rt before the addition of further TMAD (47 mg, 0.28mmol) and triphenyl phosphine (72 mg, 0.28 mmol) and stirring for 3 h atrt. The reaction mixture was partitioned between DCM and aqueous 1M HCland the phases separated. The aqueous phase was extracted twice with DCMand the combined organic phases concentrated in vacuo. Purification bygradient column chromatography, eluting with 10-60% EtOAc in iso-hexaneyielded the title compound (73 mg, 0.16 mmol).

LCMS (Method B): m/z 459 (M+H)+ (ES+), at 4.70 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.43 (s, 3H), 3.91 (s, 6H), 5.39 (s, 2H),6.38 (s, 2H), 7.34 (d, J=8.5, 1H), 7.44 (t, J=7.5, 1H), 7.66 (dd, J=9.5,2.3, 1H), 7.71-7.79 (m, 1H), 7.99 (dd, J=7.8, 1.3, 1H), 8.25 (d, J=2.5,1H)

Typical alkylation procedure for the preparation of examples byN-alkylation of cyclised intermediates from route 1, as exemplified bythe preparation of2-(4-methoxy-3,5-dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (115)

A solution of (IntA6) (0.40 g, 1.20 mmol), K₂CO₃ (0.33 g, 2.40 mmol) and2,4,6-trifluorobenzyl bromide (0.27 g, 1.20 mmol) in DMF (10 mL) washeated at 80° C. for 5 h with TLC monitoring (hexane:EtOAc 1:1). Afterconcentration in vacuo purification by column chromatography (10% EtOAcin hexane) yielded the title compound (0.50 g, 1.05 mmol).

LCMS (Method B): m/z 477.2 (M+H)+ (ES+), at 5.13 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.25 (s, 6H), 3.71 (s, 3H), 5.44 (s, 2H),7.01 (s, 2H), 7.21 (t, J=8.7, 2H), 7.45 (t, J=7.5, 1H), 7.73 (d, J=8.5,1H), 7.82-7.90 (m, 1H), 7.90-7.96 (m, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (81)

The title compound (0.20 g, 0.42 mmol) was prepared from (IntA6) (0.35g, 1.00 mmol), 2-chloro-6-fluorobenzyl bromide (0.34 g, 1.5 mmol) andK₂CO₃ (0.20 g, 1.5 mmol) in 1,4-Dioxane (10 mL) using the methods of(115).

LCMS (Method B): m/z 475.1, 477.2 (M+H)+ (ES+), at 5.21 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 2.25 (s, 6H), 3.71 (s, 3H), 5.48 (s, 2H),7.01 (s, 2H), 7.17-7.27 (m, 1H), 7.31-7.48 (m, 3H), 7.70 (d, J=8.2, 1H),7.80-7.88 (m, 1H), 7.93 (d, J=7.6, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(1-ethyl-1H-pyrazol-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (150)

The title compound (0.1 g, 0.23 mmol) was prepared from (IntA8) (0.14 g,0.47 mmol), 2-chloro-6-fluorobenzyl bromide (0.10 g, 0.47 mmol) andK₂CO₃ (0.08 g, 0.62 mmol) in DMF (3 mL) using the methods of (115).

LCMS (Method B): m/z 435.1, 437.2 (M+H)+ (ES+), at 4.07 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 1.39 (t, J=7.3, 3H), 4.17 (q, J=7.3, 2H),5.49 (s, 2H), 7.15-7.27 (m, 1H), 7.30-7.56 (m, 4H), 7.69 (d, J=8.5, 1H),7.80-7.91 (m, 1H), 7.95 (d, J=7.9, 1H), 8.08 (s, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-[5-(methylsulfanyl)pyridin-3-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (151)

The title compound (0.06 g, 0.13 mmol) was prepared from (IntA9) (0.1 g,0.31 mmol), 2-chloro-6-fluorobenzyl bromide (0.07 g, 0.34 mmol) andK₂CO₃ (0.06 g, 0.46 mmol) in DMF (10 mL) using the methods of (115).

LCMS (Method B): m/z 464.1, 466.1 (M+H)+ (ES+), at 4.51 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 2.56 (s, 3H), 5.52 (br s, 2H), 7.15-7.53 (m,4H), 7.66-7.79 (m, 2H), 7.84-7.93 (m, 1H), 7.98 (d, J=7.6, 1H), 8.32 (s,1H), 8.61 (s, 1H)

2-[5-(Methylsulfanyl)pyridin-3-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (152)

The title compound (0.05 g, 0.11 mmol) was prepared from (IntA9) (0.1 g,0.31 mmol), 2,4,6-trifluorobenzyl bromide (0.07 g, 0.34 mmol) and K₂CO₃(0.06 g, 0.46 mmol) in DMF (10 mL) using the methods of (115).

LCMS (Method B): m/z 466.1 (M+H)+ (ES+), at 4.45 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 2.56 (s, 3H), 5.47 (s, 2H), 7.23 (t, J=8.9,2H), 7.48 (t, J=7.6, 1H), 7.70-7.84 (m, 2H), 7.90 (t, J=7.6, 1H), 7.98(d, J=7.6, 1H), 8.32 (d, J=1.5, 1H), 8.62 (d, J=1.5, 1H)

2-[6-(Methylsulfanyl)pyridin-3-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (160)

The title compound (0.1 g, 0.21 mmol) was prepared from (IntA10) (0.2 g,0.21 mmol), K₂CO₃ (0.26 g, 1.86 mmol) and 2,4,6-trifluorobenzyl bromide(0.16 g, 0.68 mmol) in DMF (10 mL) using the methods of (115).

LCMS (Method B): m/z 466.1 (M+H)+ (ES+), at 4.80 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 2.56 (s, 3H), 5.47 (s, 2H), 7.22 (t, J=8.7,2H), 7.43-7.55 (m, 2H), 7.68 (dd, J=8.5, 2.4, 1H), 7.76 (d, J=8.5, 1H),7.85-7.93 (m, 1H), 7.95-8.03 (m, 1H), 8.38 (d, J=2.1, 1H)

2-(3,4-Dimethoxyphenyl)-4-(2-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (67)

The title compound (64 mg, 0.14 mmol) was prepared from (IntA1) (67 mg,0.20 mmol), K₂CO₃ (83 mg, 0.60 mmol) and 2-fluorobenzyl bromide (45 mg,0.24 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 443 (M+H)+ (ES+), at 3.98 min, 100%

¹H NMR: (400 MHz, CDCl₃) δ: 3.91 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H),6.96-6.98 (m, 2H), 7.05-7.13 (m, 3H), 7.19-7.29 (m, 3H), 7.33 (t, J=7.5,1H), 7.60 (t, J=7.3, 1H), 7.96 (d, J=7.8, 1H)

4-(2,6-Dichlorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (68)

The title compound (52 mg, 0.11 mmol) was prepared from (IntA1) (67 mg,0.20 mmol), K₂CO₃ (83 mg, 0.60 mmol) and 2,6-dichlorobenzyl chloride (47mg, 0.24 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 493/495 (M+H)+ (ES+), at 4.26 min, 100%

¹H NMR: (400 MHz, CDCl₃) δ: 3.88 (s, 3H), 3.92 (s, 3H), 5.64 (s, 2H),6.87 (d, J=2.5, 1H), 6.94 (d, J=8.5, 1H), 7.02 (dd, J=8.5, 2.3, 1H),7.15-7.19 (m, 1H), 7.28-7.33 (m, 3H), 7.50 (d, J=8.3, 1H), 7.60-7.64 (t,J=7.3, 1H), 7.92 (d, J=7.8, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (69)

The title compound (61 mg, 0.13 mmol) was prepared from (IntA11) (67 mg,0.20 mmol), K₂CO₃ (83 mg, 0.60 mmol) and 2-chloro-6-fluorobenzyl bromide(54 mg, 0.24 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 477/479 (M+H)+ (ES+), at 4.42 min, 100%

¹H NMR: (400 MHz, CDCl₃) δ: 3.80 (s, 6H), 5.55 (s, 2H), 6.58 (s, 3H),6.95-7.01 (m, 1H), 7.19-7.23 (m, 2H), 7.30 (t, J=7.3, 1H), 7.44 (d,J=8.3, 1H), 7.63 (t, J=7.3, 1H), 7.92 (d, J=7.8, 1H)

4-(2,6-Dichlorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (70)

The title compound (38 mg, 0.08 mmol) was prepared from (IntA11) (67 mg,0.20 mmol), K₂CO₃ (83 mg, 0.60 mmol) and 2,6-dichlorobenzyl chloride (47mg, 0.24 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 493/495 (M+H)+ (ES+), at 4.63 min, 100%

¹H NMR: (400 MHz, CDCl₃) δ: 3.79 (s, 6H), 5.63 (s, 2H), 6.55-6.56 (m,3H), 7.17 (t, J=8.3, 1H), 7.27-7.38 (m, 3H), 7.50 (d, J=8.3, 1H), 7.62(dt, J=7.3, 1.2, 1H), 7.91 (dd, J=7.8, 1.2, 1H)

4-(3-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (71)

The title compound (35 mg, 0.07 mmol) was prepared from (IntA1) (50 mg,0.15 mmol), K₂CO₃ (62 mg, 0.45 mmol) and 3-chloro-2-fluorobenzyl bromide(40 mg, 0.18 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 477 (M+H)+ (ES+), at 4.43 min, 100%

¹H NMR: (400 MHz, CDCl₃) δ: 3.90 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H),6.94-6.97 (m, 2H), 7.01-7.07 (m, 2H), 7.11 (t, J=6.3, 1H), 7.19 (d,J=8.3, 1H), 7.31-7.37 (m, 2H), 7.63 (t, J=7.3, 1H), 7.97 (d, J=7.8, 1H)

4-(4-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (72)

The title compound (43 mg, 0.09 mmol) was prepared from (IntA1) (50 mg,0.15 mmol), K₂CO₃ (62 mg, 0.45 mmol) and 4-chloro-2-fluorobenzyl bromide(40 mg, 0.18 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 477 (M+H)+ (ES+), at 4.50 min, 100%

¹H NMR: (400 MHz, CDCl₃) δ: 3.90 (s, 3H), 3.93 (s, 3H), 5.39 (s, 2H),6.94-6.97 (m, 2H), 7.04-7.10 (m, 2H), 7.14-7.20 (m, 3H), 7.35 (t, J=7.8,1H), 7.62 (t, J=8.5, 1H), 7.96 (t, J=7.8, 1H)

4-[(3,5-Dimethylpyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (86)

The title compound (89 mg, 0.20 mmol) was prepared from (IntA1) (167 mg,0.50 mmol), K₂CO₃ (207 mg, 1.5 mmol) and2-(chloromethyl)-3,5-dimethylpyridine (93 mg, 0.6 mmol) in DMF (5 mL)using the methods of (115).

LCMS (Method B): m/z 454 (M+H)+ (ES+), at 3.97 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.22 (s, 3H), 2.36 (s, 3H), 3.74 (s, 3H),3.82 (s, 3H), 5.36 (s, 2H), 6.88 (s, 1H), 6.96 (d, J=8.3, 1H), 7.09 (d,J=8.5, 1H), 7.30-7.47 (m, 3H), 7.72 (t, J=7.5, 1H), 7.96 (d, J=7.8, 1H),8.08 (s, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (109)

The title compound (186 mg, 0.39 mmol) was prepared from (IntA12) (160mg, 0.50 mmol), K₂CO₃ (207 mg, 1.5 mmol) and2,6-difluoro-4-methoxybenzyl bromide (142 mg, 0.6 mmol) in DMF (5 mL)using the methods of (115).

LCMS (Method B): m/z 477 (M+H)+ (ES+), at 4.86 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.51 (s, 3H), 3.75 (s, 3H), 5.42 (s, 2H),6.72-6.77 (m, 2H), 7.15 (d, J=7.5, 1H), 7.20 (s, 1H), 7.40-7.51 (m, 3H),7.72 (d, J=8.5, 1H), 7.86 (t, J=7.3, 1H), 7.93 (d, J=7.8, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (138)

The title compound (99 mg, 0.21 mmol) was prepared from (IntA5) (92 mg,0.30 mmol), K₂CO₃ (124 mg, 0.9 mmol) and 2,6-difluoro-4-methoxybenzylbromide (85 mg, 0.36 mmol) in DMF (3 mL) using the methods of (115).

LCMS (Method B): m/z 462 (M+H)+ (ES+), at 4.38 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.82 (s, 3H), 5.42 (s, 2H),6.70-6.77 (m, 2H), 7.00 (d, J=8.3, 1H), 7.06 (d, J=7.5, 1H), 7.45 (t,J=7.5, 1H), 7.76 (d, J=8.3, 1H), 7.84-7.93 (m, 3H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (140)

The title compound (179 mg, 0.39 mmol) was prepared from (IntA4) (152mg, 0.50 mmol), K₂CO₃ (207 mg, 1.5 mmol) and2,6-difluoro-4-methoxybenzyl bromide (142 mg, 0.6 mmol) in DMF (5 mL)using the methods of (115).

LCMS (Method B): m/z 462 (M+H)+ (ES+), at 4.49 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H),6.70-6.77 (m, 2H), 6.85 (dd, J=1.5, 1H), 7.03 (dd, J=5.5, 1.7, 1H), 7.46(t, J=7.5, 1H), 7.75 (d, J=8.5, 1H), 7.88 (t, J=7.3, 1H), 7.95 (d,J=7.8, 1H), 8.34 (d, J=5.5, 1H)

4-[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (83)

The title compound (41 mg, 0.10 mmol) was prepared from (IntA12) (48 mg,0.15 mmol), K₂CO₃ (62 mg, 0.45 mmol) and5-(chloromethyl)-1,3-dimethyl-1H-pyrazole (26 mg, 0.18 mmol) in DMF (2mL) using the methods of (115).

LCMS (Method B): m/z 429 (M+H)+ (ES+), at 3.72 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.03 (s, 3H), 2.05 (s, 3H), 3.76 (s, 3H),5.42 (s, 2H), 5.92 (s, 1H), 7.22 (d, J=8.3, 1H), 7.29 (s, 1H), 7.42-7.51(m, 3H), 7.68 (d, J=8.5, 1H), 7.84 (m, 1H), 7.98 (d, J=7.8, 1H)

4-(Cyclobutylmethyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (61)

The title compound (37 mg, 0.10 mmol) was prepared from (IntA12) (64 mg,0.2 mmol), K₂CO₃ (83 mg, 0.6 mmol) and (bromomethyl)cyclobutane (36 mg,0.24 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 389 (M+H)+ (ES+), at 4.67 min, 93%

¹H NMR: (400 MHz, DMSO) δ: 1.69-1.86 (m, 4H), 1.89-2.00 (m, 2H), 2.49(s, 3H), 2.67 (quin, J=7.5, 1H), 4.27 (d, J=7.0, 2H), 7.18 (d, J=7.8,1H), 7.21-7.24 (m, 1H), 7.38-7.51 (m, 3H), 7.77 (d, J=8.5, 1H),7.82-7.89 (m, 1H), 7.95 (dd, J=8.0, 1.3, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-{3-[(trifluoromethyl)sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (73)

The title compound (33 mg, 0.06 mmol) was prepared from (IntA14) (45 mg,0.12 mmol), K₂CO₃ (50 mg, 0.36 mmol) and 2-chloro-6-fluorobenzyl bromide(31 mg, 0.14 mmol) in DMF (1.5 mL) using the methods of (115).

LCMS (Method B): m/z 517/519 (M+H)+ (ES+), at 5.29 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 5.51 (s, 2H), 7.20-7.28 (m, 1H), 7.33-7.43(m, 2H), 7.46 (t, J=7.5, 1H), 7.62-7.68 (m, 1H), 7.69-7.78 (m, 3H),7.84-7.93 (m, 2H), 7.97 (dd, J=7.8, 1.3, 1H)

4-(2,6-Difluorobenzyl)-2-{3-[(trifluoromethyl)sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (75)

The title compound (32 mg, 0.06 mmol) was prepared from (IntA14) (50 mg,0.13 mmol), K₂CO₃ (55 mg, 0.40 mmol) and 2,6-difluorobenzyl bromide (33mg, 0.16 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z No ionisation observed, at 5.57 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 5.52 (s, 2H), 7.11 (t, J=8.2, 2H), 7.36-7.44(m, 1H), 7.46 (t, J=7.7, 1H), 7.63-7.68 (m, 1H), 7.70-7.79 (m, 3H),7.85-7.94 (m, 2H), 7.97 (dd, J=7.8, 1.3, 1H)

2-(3,4-Dimethoxyphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (105)

The title compound (29 mg, 0.06 mmol) was prepared from (IntA1) (84 mg,0.25 mmol), K₂CO₃ (104 mg, 0.75 mmol) and 2,4,6-trifluorobenzyl bromide(68 uL, 0.30 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 478 (M+H)+ (ES+), at 4.43 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.82 (s, 3H), 5.46 (s, 2H),6.87 (d, J=2.3, 1H), 6.92 (dd, J=8.5, 2.3, 1H), 7.08 (d, J=8.8, 1H),7.22 (t, J=8.8, 2H), 7.45 (t, J=7.5, 1H), 7.73 (d, J=8.5, 1H), 7.82-7.90(m, 1H), 7.94 (dd, J=8.0, 1.3, 1H)

2-(3,4-Dimethoxyphenyl)-4-(2,6-difluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (108)

The title compound (59 mg, 0.12 mmol) was prepared from (IntA1) (84 mg,0.25 mmol), K₂CO₃ (104 mg, 0.75 mmol) and 2,6-difluoro-4-methoxybenzylbromide (71 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 491 (M+H)+ (ES+), at 4.47 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.73 (s, 3H), 3.75 (s, 3H), 3.82 (s, 3H),5.42 (s, 2H), 6.74 (d, J=10.3, 2H), 6.87 (d, J=2.3, 1H), 6.93 (dd,J=8.5, 2.3, 1H), 7.09 (d, J=8.5, 1H), 7.43 (t, J=7.7, 1H), 7.70 (d,J=8.3, 1H), 7.81-7.88 (m, 1H), 7.93 (dd, J=7.8, 1.3, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (122)

The title compound (79 mg, 0.18 mmol) was prepared from (IntA15) (75 mg,0.25 mmol), K₂CO₃ (104 mg, 0.75 mmol) and 2-chloro-6-fluorobenzylbromide (67 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 448, 450 (M+H)+ (ES+), at 4.24 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.92 (s, 3H), 5.52 (s, 2H), 7.00 (d, J=8.8,1H), 7.23 (ddd, J=9.8, 7.8, 1.8, 1H), 7.33-7.43 (m, 2H), 7.46 (t, J=7.7,1H), 7.68-7.76 (m, 2H), 7.83-7.90 (m, 1H), 7.98 (dd, J=7.8, 1.3, 1H),8.15 (d, J=2.5, 1H)

4-(2-Chloro-6-fluorobenzyl)-6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (76)

A solution of (IntA16) (780 mg, 2.50 mmol) and triphosgene (245 mg, 0.82mmol) in 1,4-dioxane (40 mL) was divided equally into two sealed tubesand both heated at 100° C. for 8.5 h before combination andconcentration in vacuo. Purification by gradient flash chromatography,eluting with eluting with 5-40% EtOAc in heptane yielded6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (220 mg, approximately 60% purity by LCMS analysis) whichwas used without further purification.

LCMS (Method B): m/z 337.1 (M−H)− (ES−), at 2.21 min, 60%

The title compound (74 mg, 0.15 mmol) was subsequently prepared from6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (110 mg), K₂CO₃ (180 mg, 1.30 mmol) and2-chloro-6-fluorobenzyl bromide (89 uL, 0.65 mmol) in DMF (5 mL) usingthe methods of (115).

LCMS (Method B): m/z 481 (M+H)+ (ES+), at 5.33 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.49 (s, 3H), 5.47 (s, 2H), 7.13 (d, J=7.8,1H), 7.18 (br s, 1H), 7.23-7.49 (m, 6H), 7.70 (dd, J=11.0, 2.0, 1H),8.06 (dd, J=8.8, 5.8, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (136)

The title compound (58 mg, 0.13 mmol) was prepared from (IntA15) (76 mg,0.25 mmol), K₂CO₃ (104 mg, 0.75 mmol) and 2,6-difluoro-4-methoxybenzylbromide (71 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 462 (M+H)⁺ (ES⁺), at 4.62 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.92 (s, 3H), 5.43 (s, 2H),6.75 (d, J=10.3, 2H), 7.01 (d, J=8.8, 1H), 7.46 (t, J=7.7, 1H),7.67-7.77 (m, 2H), 7.83-7.92 (m, 1H), 7.96 (dd, J=7.8, 1.3, 1H), 8.15(d, J=2.5, 1H)

2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (145)

The title compound (103 mg, 0.21 mmol) was prepared from (IntA19) (84mg, 0.25 mmol), K₂CO₃ (104 mg, 0.75 mmol) and 2,4,6-trifluorobenzylbromide (68 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 480 (M+H)+ (ES+), at 4.25 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.78 (s, 3H), 3.94 (s, 3H), 5.47 (s, 2H),7.22 (t, J=8.8, 2H), 7.27 (d, J=2.3, 1H), 7.47 (t, J=7.5, 1H), 7.72 (d,J=2.0, 1H), 7.76 (d, J=8.5, 1H), 7.85-7.93 (m, 1H), 7.97 (dd, J=7.8,1.3, 1H)

4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (146)

The title compound (97 mg, 0.20 mmol) was prepared from (IntA19) (84 mg,0.25 mmol), K₂CO₃ (104 mg, 0.75 mmol) and 2,6-difluoro-4-methoxybenzylbromide (71 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).

LCMS (Method B): m/z 492 (M+H)+ (ES+), at 4.39 min, 99%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.78 (s, 3H), 3.94 (s, 3H),5.43 (s, 2H), 6.74 (d, J=10.0, 2H), 7.27 (d, J=2.0, 1H), 7.45 (t, J=7.7,1H), 7.70-7.77 (m, 2H), 7.82-7.91 (m, 1H), 7.95 (dd, J=7.8, 1.3, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (153)

The title compound (38 mg, 0.08 mmol) was prepared from (IntA20) (84 mg,0.25 mmol), 2,6-difluoro-4-methoxybenzyl bromide (71 mg, 0.30 mmol) andK₂CO₃ (104 mg, 0.75 mmol) using the methods of (115).

LCMS (Method B): m/z 492 (M+H)⁺ (ES⁺), at 4.26 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H),5.41 (s, 2H), 6.73 (d, J=10.3, 2H), 7.03 (d, J=8.0, 1H), 7.40-7.50 (m,2H), 7.73 (d, J=8.5, 1H), 7.82-7.88 (m, 1H), 7.91 (d, J=7.8, 1H)

2-(5,6-Dimethoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (147)

The title compound (62 mg, 0.13 mmol) was prepared from (IntA20) (84 mg,0.25 mmol), 2,4,6-trifluorobenzyl bromide (68 mg, 0.30 mmol) and K₂CO₃(104 mg, 0.75 mmol) using the methods of (115).

LCMS (Method B): m/z 480 (M+H)+ (ES+), at 4.32 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H),5.41 (s, 2H), 6.73 (d, J=10.3, 2H), 7.03 (d, J=8.0, 1H), 7.39-7.50 (m,2H), 7.71-7.77 (m, 1H), 7.81-7.88 (m, 1H), 7.91 (d, J=7.8, 1H)

2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (148)

The title compound (103 mg, 0.21 mmol) was prepared from (IntA21,) (84mg, 0.25 mmol), 2,4,6-trifluorobenzyl bromide (68 mg, 0.30 mmol) andK₂CO₃ (104 mg, 0.75 mmol) using the methods of (115).

LCMS (Method B): m/z 480 (M+H)+ (ES⁺), at 4.95 min, 99%

¹H NMR: (400 MHz, DMSO) δ: 3.91 (s, 6H), 5.45 (s, 2H), 6.38 (s, 2H),7.21 (t, J=8.8, 2H), 7.47 (t, J=7.7, 1H), 7.76 (d, J=8.5, 1H), 7.84-7.92(m, 1H), 7.95 (dd, J=7.9, 1.1, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (149)

The title compound (92 mg, 0.19 mmol) was prepared from (IntA21) (84 mg,0.25 mmol), 2,6-difluoro-4-methoxybenzyl bromide (71 mg, 0.30 mmol) andK₂CO₃ (104 mg, 0.75 mmol) using the methods of (115).

LCMS (Method B): m/z 492 (M+H)+ (ES+), at 4.98 min, 99%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.91 (s, 6H), 5.41 (s, 2H),6.39 (s, 2H), 6.74 (d, J=10.3, 2H), 7.45 (t, J=7.7, 1H), 7.73 (d, J=8.5,1H), 7.83-7.90 (m, 1H), 7.94 (dd, J=7.8, 1.3, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (166)

The title compound (48 mg, 0.10 mmol) was prepared from (IntA21) (101mg, 0.34 mmol), 2-chloro-6-fluorobenzyl bromide (80 mg, 0.36 mmol) andK₂CO₃ (124 mg, 0.9 mmol) in DMF (1.5 mL) using the methods of (115).

LCMS (Method B): m/z 480, 478 (M+H)+ (ES+), at 5.16 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.90 (s, 6H), 5.49 (s, 2H), 6.38 (s, 2H),7.19-7.27 (m, 1H), 7.31-7.42 (m, 2H), 7.45 (t, J=7.7, 1H), 7.73 (d,J=8.5, 1H), 7.82-7.91 (m, 1H), 7.96 (dd, J=7.8, 1.3, 1H)

4-(2,6-Difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (167)

The title compound (45 mg, 0.10 mmol) was prepared from (IntA21) (101mg, 0.34 mmol), 2,6-difluorobenzyl bromide (75 mg, 0.36 mmol) and K₂CO₃(124 mg, 0.9 mmol) in DMF (1.5 mL) using the methods of (115).

LCMS (Method B): m/z 462 (M+H)+ (ES+), at 4.95 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.91 (s, 6H), 5.49 (s, 2H), 6.39 (s, 2H),7.10 (t, J=8.2, 2H), 7.35-7.50 (m, 2H), 7.75 (d, J=8.5, 1H), 7.83-7.91(m, 1H), 7.95 (dd, J=7.8, 1.3, 1H)

4-(2,6-Difluoro-4-hydroxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (116)

A solution of (IntA27) (533 mg, 0.90 mmol) in glacial aceticacid/THF/H₂O (3:1:1, 20 mL) was stirred at rt for 22 h before furtherglacial acetic acid (6 mL) was added. After stirring for 4 d, furtherglacial acetic acid (6 mL) was added and the mixture stirred at rt for15.5 h then at 50° C. for 1 d. After concentration in vacuo,purification by gradient column chromatography, eluting with 10-70%EtOAc in iso-hexane yielded the title compound (75 mg, 0.16 mmol).

LCMS (Method B): m/z 477 (M+H)+ (ES+), at 2.15 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.76 (s, 3H), 3.86 (s, 3H), 5.41 (s, 2H),6.47 (d, J=10.0, 2H), 6.91 (d, J=2.5, 1H), 6.97 (dd, J=8.5, 2.3, 1H),7.12 (d, J=8.5, 1H), 7.46 (t, J=7.7, 1H), 7.72 (d, J=8.3, 1H), 7.84-7.91(m, 1H), 7.95 (dd, J=7.8, 1.3, 1H), 10.5 (br. s, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-[3-(methylsulfonyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (111)

A mixture of 3-chloroperoxybenzoic acid (approximately 70% purity, 60mg, approximately 0.22 mmol) and (109) (48 mg, 0.1 mmol) in DCM (1 mL)was stirred at rt for 3 h. DCM (10 mL) and saturated aqueous sodiumcarbonate (5 mL) were added, the phases were separated and the organicphase concentrated in vacuo to yield the title compound (46 mg, 0.09mmol).

LCMS (Method B): m/z 509 (M+H)+/526 (M+18)+(ES+), at 4.16 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.32 (s, 3H), 3.33 (s, 3H), 5.43 (s, 2H),6.68-6.81 (m, 2H), 7.47 (t, J=7.7, 1 H), 7.72-7.82 (m, 2H), 7.82-8.00(m, 4H), 8.13 (d, J=7.8, 1H)

2-[3-(Methylsulfonyl)phenyl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (112)

2-[3-(methylsulfanyl)phenyl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (212 mg, 0.45 mmol) was prepared from (IntA12) (160 mg, 0.5mmol), 2,4,6-trifluorobenzyl bromide (135 mg, 0.6 mmol) and K₂CO₃ (207mg, 1.5 mmol) in DMF (5 mL) using the methods of (115).

The title compound (46 mg, 0.09 mmol) was then prepared from2-[3-(methylsulfanyl)phenyl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (46 mg, 0.1 mmol), and 3-chloroperoxybenzoic acid(approximately 70% purity, 60 mg, approximately 0.22 mmol) using themethods of (111).

LCMS (Method B): m/z 497 (M+H)+/514 (M+18)+(ES+), at 4.09 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.31 (s, 3H), 5.47 (s, 2H), 7.19-7.26 (m,2H), 7.48 (t, J=7.5, 1H), 7.75-7.80 (m, 2H), 7.83-7.94 (m, 3H), 7.98 (d,J=7.8, 1H), 8.13 (d, J=8.0, 1H)

2-(4-Hydroxy-3,5-dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (114)

To a solution of (115) (0.2 g, 0.42 mmol) in DCM (5 mL) was added borontribromide (1.0M solution in DCM, 0.46 mL, 0.46 mmol) at −70° C. Theresulting mixture was stirred for approximately two h at rt with TLCmonitoring (hexane:EtOAc, 1:1). The reaction mixture was poured intosaturated aqueous NaHCO₃ solution (50 mL), extracted with EtOAc (3×50mL), and the combined organic layer was dried over Na₂SO₄ andconcentrated in vacuo. Purification by trituration with DCM in pentane(1:9) yielded the title compound (0.11 g, 0.24 mmol).

LCMS (Method B): m/z 463.2 (M+H)+ (ES+), at 4.12 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.18 (s, 6H), 5.43 (s, 2H), 6.88 (s, 2H),7.21 (t, J=8.7, 2H), 7.43 (t, J=7.6, 1H), 7.70 (d, J=8.5, 1H), 7.79-7.88(m, 1H), 7.92 (dd, J=7.9, 1.2, 1H), 8.76 (s, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (82)

The title compound (0.12 g, 0.26 mmol) was prepared from (81) (0.23 g,0.48 mmol) and boron tribromide (1.0M solution in DCM, 0.60 mL, 0.60mmol) using the methods of (114).

LCMS (Method B): m/z 461.1, 463.2 (M+H)+ (ES+), at 4.22 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.18 (s, 6H), 5.48 (s, 2H), 6.88 (s, 2H),7.14-7.28 (m, 1H), 7.31-7.49 (m, 3H), 7.67 (d, J=8.2, 1H), 7.83 (t,J=7.3, 1H), 7.92 (d, J=7.6, 1H), 8.74 (s, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (171)

The title compound (60 mg, 0.13 mmol) was prepared from2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA28) (161 mg, 0.50 mmol), 2,6-difluoro-4-methoxybenzylbromide (179 mg, 0.76 mmol) and K₂CO₃ (104 mg, 0.75 mmol) in DMF (3 mL)using the methods of (115).

LCMS (Method B): m/z 476.1 (M+H)+ (ES+), at 4.90 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.15 (s, 3H), 3.71 (s, 3H), 3.90 (s, 3H),5.38 (s, 2H), 6.60-6.81 (m, 2H), 7.41 (t, J=7.6, 1H), 7.54 (dd, J=2.3,0.9, 1H), 7.68 (d, J=8.2, 1H), 7.83 (td, J=7.9, 1.6, 1H), 7.87-8.00 (m,2H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (178)

The title compound (58 mg, 0.13 mmol) was prepared from2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA29) (150 mg, 0.49 mmol), 2,6-difluoro-4-methoxybenzylbromide (129 mg, 0.54 mmol) and K₂CO₃ (102 mg, 0.74 mmol) in DMF (3 mL)at 50° C. using the methods of (115).

LCMS (Method B): m/z 460.0 (M+H)+ (ES+), at 4.32 min, 95%

¹H NMR: (400 MHz, CDCl₃) δ: 2.38 (s, 3H), 2.60 (s, 3H), 3.77 (s, 3H),5.45 (s, 2H), 6.43-6.51 (m, 2H), 7.35 (t, J=7.5, 1H), 7.49-7.51 (m, 1H),7.62-7.73 (m, 2H), 7.93 (dd, J=7.8, 1.5, 1H), 8.37 (d, J=2.3, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-2-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (179)

Step 1: Preparation of tert-butyl{6-[4-(2,6-difluoro-4-methoxybenzyl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl]-3-methoxypyridin-2-yl}methylcarbamate

The title compound (301 mg, 0.51 mmol) was prepared from tert-butyl[6-(1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl)-3-methoxypyridin-2-yl]methylcarbamate(IntA31) (343 mg, 0.79 mmol), 2,6-difluoro-4-methoxybenzyl bromide (225mg, 0.95 mmol) and K₂CO₃ (164 mg, 1.19 mmol) in DMF (4 mL) at 11 usingthe methods of (115).

LCMS (Method B): m/z 591.2 (M+H)+ (ES+), at 5.04 min, 100%

Step 2: Preparation of4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-2-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide A solution of tert-butyl{6-[4-(2,6-difluoro-4-methoxybenzyl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl]-3-methoxypyridin-2-yl}methylcarbamate(295 mg, 0.50 mmol) and TFA (2 mL) in DCM (3 mL) was stirred at rt for 2h before concentration in vacuo. DCM and saturated aqueous NaHCO₃solution (5 mL each) were added and the phases were separated. Theorganic phase was extracted with DCM (2×5 mL) and the combined organicphases were concentrated in vacuo. Purification by gradient columnchromatography, eluting with 15-80% EtOAc in iso-hexane yielded thetitle compound (132 mg, 0.27 mmol) as a white solid.

LCMS (Method B): m/z 491.1 (M+H)+ (ES+), at 4.37 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.67 (d, J=4.6, 3H), 3.71 (s, 3H), 3.80 (s,3H), 5.36 (s, 2H), 6.38 (q, J=4.6, 1H), 6.47 (d, J=7.8, 1H), 6.58-6.80(m, 2H), 7.04 (d, J=7.8, 1H), 7.38 (t, J=7.6, 1H), 7.67 (d, J=8.2, 1H),7.73-7.90 (m, 2H)

2-(4,5-Dimethoxypyrimidin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (170)

The title compound was prepared from2-(4,5-dimethoxypyrimidin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA32) (50 mg, 0.15 mmol), 2,4,6-trifluorobenzyl bromide(41 mg, 0.18 mmol) and K₂CO₃ (62 mg, 0.45 mmol) in DMF (1.5 mL) usingthe methods of (115). After purification by gradient columnchromatography further purification by preparative HPLC (method C)yielded the title compound (8 mg, 0.02 mmol).

LCMS (Method B): m/z 481.0 (M+H)+ (ES+), at 4.12 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 3.91 (s, 3H), 3.95 (s, 3H), 5.46 (s, 2H),7.21 (t, J=8.7, 2H), 7.47 (t, J=7.5, 1H), 7.79 (d, J=8.5, 1H), 7.88 (dt,J=8.7, 1.5, 1H), 7.93 (dd, J=7.9, 1.1, 1H), 8.34 (s, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(4,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (183)

The title compound was prepared from2-(4,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (IntA33) (101 mg, 0.3 mmol), 2,6-difluoro-4-methoxybenzylbromide (85 mg, 0.36 mmol) and K₂CO₃ (124 mg, 0.9 mmol) in DMF (1.5 mL)using the methods of (115). After trituration with Et₂O furtherpurification by preparative HPLC (method C) yielded the title compound(7 mg, 0.01 mmol).

LCMS (Method B): m/z 492.1 (M+H)+ (ES+), at 4.66 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.80 (s, 3H), 3.85 (s, 3H),5.41 (s, 2H), 6.52 (d, J=1.8, 1H), 6.65 (d, J=1.8, 1H), 6.73 (d, J=10.3,2H), 7.44 (t, J=7.5, 1H), 7.75 (d, J=8.3, 1H), 7.83-7.88 (m, 1H), 7.91(dd, J=7.8, 1.3, 1H)4-(2,6-Difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (181) The title compound (120 mg, 0.24 mmol) was prepared intwo steps from tert-butyl[5-(1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl)-2-methoxypyridin-3-yl]methylcarbamate(IntA35) (130 mg, 0.3 mmol), 2,6-difluoro-4-methoxybenzyl bromide (85mg, 0.36 mmol) and K₂CO₃ (124 mg, 0.9 mmol) in DMF (1.5 mL); followed byTFA (2 mL) in DCM (3 mL) at rt using the methods of (179).

LCMS (Method B): m/z 491.1 (M+H)+ (ES+), at 4.46 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.62 (d, J=4.6, 3H), 3.70 (s, 3H), 3.90 (s,3H), 5.38 (s, 2H), 5.69 (d, J=4.6, 1H), 6.51 (s, 1H), 6.71 (d, J=10.1,2H), 7.27 (s, 1H), 7.39 (t, J=7.6, 1H), 7.66 (d, J=8.7, 1H), 7.81 (t,J=7.8, 1H), 7.89 (d, J=7.8, 1H)

Route 24-(2-Chloro-6-fluorobenzyl)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (132)

A mixture of (IntB1) (151 mg), 1,1′-carbonyldiimidazole (232 mg, 1.4mmol) and triethylamine (0.1 mL, 0.70 mmol) in DMF (1 mL) was heated at100° C. in a sealed tube for 4 h. After concentration in vacuo,purification by gradient column chromatography eluting with 0-5% MeOH inDCM yielded the title compound (17 mg, 0.04 mmol).

LCMS (Method B): m/z 448 (M+H)+ (ES+), at 3.53 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.46 (s, 3H), 5.50 (s, 2H), 6.48 (d, J=9.5,1H), 7.23 (ddd, J=9.5, 7.8, 1.5, 1H), 7.31-7.41 (m, 3H), 7.45 (t, J=7.7,1H), 7.71 (d, J=8.5, 1H), 7.82-7.89 (m, 1H), 7.97 (dd, J=7.8, 1.3, 1H),8.02 (d, J=2.8, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(2-methoxypyrimidin-5-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (137)

The title compound (40 mg, 0.09 mmol) was prepared from (IntB2) (106mg), 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) and triethylamine (0.07mL, 0.50 mmol) using the methods of (132).

LCMS (Method B): m/z 449 (M+H)+ (ES+), at 4.22 min, 99%

¹H NMR: (400 MHz, DMSO) δ: 4.00 (s, 3H), 5.53 (s, 2H), 7.19-7.28 (m,1H), 7.31-7.44 (m, 2H), 7.48 (t, J=7.5, 1H), 7.75 (d, J=8.5, 1H),7.84-7.93 (m, 1H), 8.01 (dd, J=7.8, 1.3, 1H), 8.67 (s, 2H)

4-(2-Chloro-6-fluorobenzyl)-7-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (74)

The title compound (81 mg, 0.17 mmol) was prepared from (IntB4) (119 mg,0.26 mmol), 1,1′-carbonyldiimidazole (169 mg, 1.0 mmol) andtriethylamine (0.07 mL, 0.50 mmol) using the methods of (132).

LCMS (Method B): m/z 481, 483 (M+H)+ (ES+), at 4.89 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 5.51 (s, 2H), 7.13-7.21 (m, 3H), 7.32-7.49(m, 4H), 7.67-7.79 (m, 3H)

4-(2-Chloro-6-fluorobenzyl)-5-fluoro-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (123)

The title compound (130 mg, 0.28 mmol) was prepared from (IntB5) (139mg, 0.32 mmol), 1,1′-carbonyldiimidazole (205 mg, 1.3 mmol) andtriethylamine (88 uL, 0.64 mmol) using the methods of (132).

LCMS (Method B): m/z 466, 468 (M+H)+ (ES+), at 4.72 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 3.89 (s, 3H), 5.42 (s, 2H), 6.96 (d, J=8.8,1H), 7.19 (t, J=8.8, 1H), 7.32-7.42 (m, 2H), 7.55-7.60 (m, 1H), 7.65(dd, J=8.8, 2.8, 1H), 7.82-7.88 (m, 2H), 8.08 (d, J=2.5, 1H)

5-Fluoro-2-(6-methoxypyridin-3-yl)-4-(2-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (130)

The title compound (127 mg, 0.30 mmol) was prepared from (IntB6) (139mg, 0.35 mmol), 1,1′-carbonyldiimidazole (225 mg, 1.4 mmol) andtriethylamine (97 uL, 0.70 mmol) using the methods of (132).

LCMS (Method B): m/z 428 (M+H)⁺ (ES⁺), at 4.81 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.32 (s, 3H), 3.91 (s, 3H), 5.32 (s, 2H),7.01 (d, J=8.8, 1H), 7.07-7.21 (m, 4H), 7.53 (td, J=8.0, 4.0, 1H), 7.73(dd, J=13.3, 8.3, 1H), 7.80 (dd, J=8.9, 2.6, 1H), 7.86 (d, J=7.5, 1H),8.23 (d, J=2.5, 1H)

7-Fluoro-4-[1-(2-fluorophenyl)ethyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (63)

A solution of (IntB3) (139 mg, 0.32 mmol) and triphosgene (32 mg, 0.11mmol) in 1,4-dioxane (6 mL) was heated in a sealed vial at 100° C. forapproximately 3 d, with the addition of further triphosgene (32 mg, 0.11mmol) after 1 d. After concentration in vacuo, purification by gradientcolumn chromatography eluting with 5-40% EtOAc in iso-hexane yielded thetitle compound (18 mg, 0.04 mmol).

LCMS (Method B): m/z 461 (M+H)+ (ES+), at 5.24 min, 95%

¹H NMR: (400 MHz, DMSO) δ: (400 MHz, DMSO) δ: 1.95 (d, J=7.0, 3H), 2.48(s, 3H), 5.93 (q, J=6.9, 1H), 7.09 (d, J=7.8, 1H), 7.15-7.23 (m, 3H),7.34-7.46 (m, 3H), 7.61 (t, J=7.5, 1H), 7.67-7.76 (m, 2H), 7.91 (dd,J=7.0, 2.8, 1H)

Route 42-(3,4-Dimethoxyphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (93) Step 1: Preparation ofN-(3,4-dimethoxyphenyl)-2-[(2,4,6-trifluorobenzyl)amino]pyridine-3-sulfonamide

A solution of (IntC1) (82 mg, 0.25 mmol) and 2,4,6-trifluorobenzyl amine(120 mg, 0.75 mmol) in acetonitrile (1.5 mL) was heated at 100° C. in aBiotage Initiator microwave reactor for 1 h. Further2,4,6-trifluorobenzyl amine (120 mg, 0.75 mmol) was added and themixture heated at 180° C. in a Biotage Initiator microwave reactor for 2h. After concentration in vacuo purification by gradient columnchromatography eluting with 15-60% EtOAc in iso-hexane yielded the titlecompound (98 mg, 0.22 mmol).

LCMS (Method B): m/z 454 (M+H)+ (ES+), at 1.22 min.

Step 2: Preparation of2-(3,4-dimethoxyphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide

The title compound (63 mg, 0.13 mmol) was prepared fromN-(3,4-dimethoxyphenyl)-2-[(2,4,6-trifluorobenzyl)amino]pyridine-3-sulfonamide(98 mg, 0.22 mmol), 1,1′-carbonyldiimidazole (143 mg, 0.88 mmol) andtriethylamine (0.06 mL, 0.44 mmol) using the methods of (132).

LCMS (Method B): m/z 480 (M+H)+ (ES+), at 4.49 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.82 (s, 3H), 5.58 (s, 2H),6.92-7.00 (m, 2H), 7.04-7.11 (m, 1H), 7.18 (t, J=8.8, 2H), 7.51 (dd,J=7.8, 5.0, 1H), 8.47 (dd, J=7.8, 1.5, 1H), 8.82 (dd, J=5.0, 1.5, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (94)

The title compound (48 mg, 0.10 mmol) was prepared in two steps from(IntC1) (82 mg, 0.25 mmol) and 2-chloro-6-fluorobenzyl amine (0.1 mL,0.75 mmol); followed by 1,1′-carbonyldiimidazole (191 mg, 1.18 mmol) andtriethylamine (0.08 mL, 0.59 mmol) using the methods of (93).

LCMS (Method B): m/z 478 (M+H)+ (ES+), at 4.55 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.82 (s, 3H), 5.63 (s, 2H),6.92-6.98 (m, 2H), 7.04-7.10 (m, 1H), 7.15-7.23 (m, 1H), 7.29-7.41 (m,2H), 7.49 (dd, J=7.8, 4.8, 1H), 8.47 (dd, J=7.8, 1.5, 1H), 8.81 (dd,J=4.9, 1.6, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (95) Step 1: Preparation of2-[(2,6-difluoro-4-methoxybenzyl)amino]-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide

A solution of (IntC1) (128 mg, 0.39 mmol) and2,4-difluoro-4-methoxybenzyl amine (404 mg, 2.34 mmol) in acetonitrile(1.5 mL) was heated at 180° C. in a Biotage Initiator microwave reactorfor 2 h. After concentration in vacuo purification by gradient columnchromatography eluting with 10-60% EtOAc in iso-hexane yielded the titlecompound (198 mg, 0.43 mmol).

LCMS (Method A): m/z 466 (M+H)+ (ES+), at 1.26 min, 95%

Step 2: Preparation of4-(2,6-difluoro-4-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide

The title compound (89 mg, 0.18 mmol) was prepared from2-[(2,6-difluoro-4-methoxybenzyl)amino]-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide(198 mg, 0.43 mmol), 1,1′-carbonyldiimidazole (279 mg, 1.72 mmol) andtriethylamine (0.12 mL, 0.86 mmol) using the methods of (132).

LCMS (Method B): m/z 492 (M+H)+ (ES+), at 4.48 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.75 (s, 3H), 3.82 (s, 3H),5.54 (s, 2H), 6.71 (d, J=10.0, 2H), 6.91-7.00 (m, 2H), 7.04-7.12 (m,1H), 7.49 (dd, J=7.8, 5.0, 1H), 8.46 (dd, J=7.8, 1.8, 1H), 8.82 (dd,J=4.9, 1.6, 1H)

4-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (96)

The title compound (16 mg, 0.03 mmol) was prepared in two steps from(IntC1) (82 mg, 0.25 mmol) and (3,5-difluoropyridin-2-yl)methanamine(108 mg, 0.75 mmol); followed by 1,1′-carbonyldiimidazole (65 mg, 0.4mmol) and triethylamine (28 uL, 0.2 mmol) using the methods of (95).

LCMS (Method B): m/z 463 (M+H)+ (ES+), at 3.86 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.74 (s, 3H), 3.83 (s, 3H), 5.63 (s, 2H),6.94 (d, J=2.5, 1H), 6.99 (dd, J=8.5, 2.2, 1H), 7.10 (d, J=8.8, 1H),7.49 (dd, J=8.0, 5.0, 1H), 7.99 (t, J=8.5, 1H), 8.37 (d, J=2.3, 1H),8.52 (d, J=7.8, 1H), 8.72 (d, J=4.8, 1H)

4-(4-Chloro-2,6-difluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (97)

The title compound (38 mg, 0.08 mmol) was prepared in two steps from(IntC1) (208 mg, 0.63 mmol), 2,6-difluoro-4-chlorobenzylamine (135 mg,0.76 mmol) and N,N-diisopropylethylamine (113 uL, 0.63 mmol); followedby 1,1′-carbonyldiimidazole (166 mg, 1.0 mmol) in DMF (8.5 mL) using themethods of (95).

LCMS (Method B): m/z 496, 498 (M+H)+ (ES+), at 4.82 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.82 (s, 3H), 5.58 (s, 2H),6.89-7.00 (m, 2H), 7.02-7.12 (m, 1H), 7.36 (d, J=7.8, 2H), 7.51 (dd,J=7.8, 4.8, 1H), 8.48 (dd, J=7.8, 1.5, 1H), 8.82 (dd, J=4.8, 1.5, 1H)

2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (98)

The title compound (82 mg, 0.17 mmol) was prepared in two steps from(IntC2) (165 mg, 0.5 mmol), 2,4,6-trifluorobenzylamine (0.18 mL, 1.5mmol); followed by 1,1′-carbonyldiimidazole (233 mg, 1.44 mmol),triethylamine (0.10 mL, 0.72 mmol) in DMF (1.5 mL) using the methods of(95).

LCMS (Method B): m/z 481 (M+H)+ (ES+), at 5.12 min, 100%

¹H NMR: (400 MHz, DMSO) S: 3.90 (s, 6H), 5.56 (s, 2H), 6.44 (s, 2H),7.17 (t, J=8.8, 2H), 7.52 (dd, J=7.8, 5.0, 1H), 8.48 (dd, J=7.8, 1.5,1H), 8.84 (dd, J=4.8, 1.5, 1H)

2-(5,6-Dimethoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (99)

The title compound (118 mg, 0.25 mmol) was prepared in two steps from(IntC3) (165 mg, 0.5 mmol), 2,4,6-trifluorobenzylamine (0.18 mL, 1.5mmol); followed by 1,1′-carbonyldiimidazole (246 mg, 1.52 mmol),triethylamine (0.11 mL, 0.76 mmol) in DMF (1.5 mL) using the methods of(95).

LCMS (Method B): m/z 481 (M+H)+ (ES+), at 4.47 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.82 (s, 3H), 3.85 (s, 3H), 5.58 (s, 2H),7.08 (d, J=8.0, 1H), 7.19 (t, J=8.8, 2H), 7.46 (d, J=8.3, 1H), 7.52 (dd,J=7.9, 4.9, 1H), 8.47 (dd, J=7.9, 1.6, 1H), 8.83 (dd, J=4.9, 1.6, 1H)

2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (100)

The title compound (159 mg, 0.33 mmol) was prepared in two steps from(IntC4) (165 mg, 0.5 mmol), 2,4,6-trifluorobenzylamine (0.18 mL, 1.5mmol); followed by 1,1′-carbonyldiimidazole (311 mg, 1.92 mmol),triethylamine (0.13 mL, 0.96 mmol) in DMF (1.5 mL) using the methods of(95).

LCMS (Method B): m/z 481 (M+H)+ (ES+), at 4.49 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.77 (s, 3H), 3.93 (s, 3H), 5.59 (s, 2H),7.19 (t, J=8.8, 2H), 7.35 (d, J=2.0, 1H), 7.53 (dd, J=7.8, 4.8, 1H),7.75 (d, J=2.0, 1H), 8.51 (dd, J=7.8, 1.8, 1H), 8.85 (dd, J=4.9, 1.6,1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (163)

The title compound (108 mg, 0.22 mmol) was prepared in two steps from(IntC2) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL,0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by1,1′-carbonyldiimidazole (246 mg, 1.52 mmol), triethylamine (0.10 mL,0.72 mmol) in DMF (1.5 mL) using the methods of (95).

LCMS (Method B): m/z 493 (M+H)+ (ES+), at 5.05 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.91 (s, 6H), 5.53 (s, 2H),6.44 (s, 2H), 6.70 (d, J=10.3, 2H), 7.51 (dd, J=7.9, 4.9, 1H), 8.47 (dd,J=7.8, 1.5, 1H), 8.84 (dd, J=4.8, 1.8, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (164)

The title compound (112 mg, 0.23 mmol) was prepared in two steps from(IntC3) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL,0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by1,1′-carbonyldiimidazole (253 mg, 1.56 mmol), triethylamine (0.11 mL,0.79 mmol) in DMF (1.5 mL) using the methods of (95).

LCMS (Method B): m/z 493 (M+H)+ (ES+), at 4.43 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.75 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H),5.54 (s, 2H), 6.70 (d, J=10.3, 2H), 7.07 (d, J=8.0, 1H), 7.46 (d, J=8.0,1H), 7.51 (dd, J=7.8, 5.0, 1H), 8.44 (dd, J=7.8, 1.8, 1H), 8.83 (dd,J=4.9, 1.6, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (165)

The title compound (134 mg, 0.27 mmol) was prepared in two steps from(IntC4) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL,0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by1,1′-carbonyldiimidazole (331 mg, 2.04 mmol), triethylamine (0.14 mL,1.00 mmol) in DMF (1.5 mL) using the methods of (95).

LCMS (Method B): m/z 493 (M+H)+ (ES+), at 4.45 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.76 (s, 3H), 3.77 (s, 3H), 3.94 (s, 3H),5.55 (s, 2H), 6.64-6.76 (m, 2H), 7.35 (d, J=2.0, 1H), 7.52 (dd, J=7.8,5.0, 1H), 7.75 (d, J=2.3, 1H), 8.48 (dd, J=7.9, 1.6, 1H), 8.84 (dd,J=4.9, 1.6, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (168)

The title compound (157 mg, 0.33 mmol) was prepared in two steps from(IntC3) (165 mg, 0.5 mmol), 2-chloro-6-fluorobenzylamine (75 uL, 0.6mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by1,1′-carbonyldiimidazole (298 mg, 1.84 mmol), triethylamine (0.13 mL,0.93 mmol) in DMF (1.5 mL) using the methods of (95).

LCMS (Method B): m/z 481, 479 (M+H)+ (ES+), at 4.57 min, 100%

¹H NMR: (400 MHz, DMSO) δ: δ 3.81 (s, 3H), 3.85 (s, 3H), 5.63 (s, 2H),7.07 (d, J=8.0, 1H), 7.14-7.23 (m, 1H), 7.28-7.42 (m, 2H), 7.45 (d,J=8.0, 1H), 7.51 (dd, J=7.8, 5.0, 1H), 8.46 (dd, J=7.8, 1.8, 1H), 8.82(dd, J=4.9, 1.6, 1H)

4-(2,6-Difluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (169)

The title compound (57 mg, 0.12 mmol) was prepared in two steps from(IntC3) (165 mg, 0.5 mmol), 2,6-difluorobenzylamine (70 uL, 0.6 mmol)and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by1,1′-carbonyldiimidazole (305 mg, 1.88 mmol), triethylamine (0.13 mL,0.93 mmol) in DMF (1.5 mL) using the methods of (95).

LCMS (Method B): m/z 463 (M+H)+ (ES+), at 4.34 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.82 (s, 3H), 3.85 (s, 3H), 5.62 (s, 2H),6.98-7.13 (m, 3H), 7.32-7.43 (m, 1H), 7.46 (d, J=8.0, 1H), 7.52 (dd,J=7.8, 5.0, 1H), 8.46 (dd, J=7.9, 1.6, 1H), 8.83 (dd, J=4.8, 1.5, 1H)

2-(3,4-Dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (101)

The title compound (64 mg, 0.14 mmol) was prepared in two steps from(IntC5) (217 mg, 0.73 mmol), 2,4,6-trifluorobenzylamine (0.11 mL, 0.88mmol) and N,N-diisopropylethylamine (261 uL, 1.46 mmol); followed by1,1′-carbonyldiimidazole (289 mg, 1.78 mmol) in DMF (7.1 mL) using themethods of (95).

LCMS (Method B): m/z 448 (M+H)+ (ES+), at 5.24 min, 98%

¹H NMR: (400 MHz, DMSO) δ: 2.26 (s, 3H), 2.29 (s, 3H), 5.57 (s, 2H),7.03-7.23 (m, 4H), 7.29 (d, J=8.0, 1H), 7.51 (dd, J=7.8, 5.0, 1H), 8.46(d, J=7.5, 1H), 8.82 (d, J=3.8, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(3,4-dimethylphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (102)

The title compound (45 mg, 0.10 mmol) was prepared in two steps from(IntC5) (217 mg, 0.73 mmol), 2,6-difluoro-4-methoxybenzylamine (125 uL,0.88 mmol) and N,N-diisopropylethylamine (261 uL, 1.46 mmol); followedby 1,1′-carbonyldiimidazole (362 mg, 2.23 mmol) in DMF (8.9 mL) usingthe methods of (95).

LCMS (Method B): m/z 460 (M+H)+ (ES+), at 5.22 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.26 (s, 3H), 2.28 (s, 3H), 3.71-3.80 (m,3H), 5.53 (s, 2H), 6.65-6.75 (m, 2H), 7.06-7.18 (m, 2H), 7.29 (d, J=8.0,1H), 7.49 (dd, J=7.9, 4.9, 1H), 8.45 (dd, J=7.8, 1.5, 1H), 8.82 (dd,J=4.8, 1.8, 1H)2-(3,5-Dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (103) The title compound (89 mg, 0.20 mmol) was prepared intwo steps from (IntC6) (209 mg, 0.71 mmol), 2,4,6-trifluorobenzylamine(107 uL, 0.88 mmol) and N,N-diisopropylethylamine (252 uL, 1.41 mmol);followed by 1,1′-carbonyldiimidazole (386 mg, 2.38 mmol) andtriethylamine (114 uL, 0.82 mmol) in DMF (9.5 mL) using the methods of(95).

LCMS (Method B): m/z 448 (M+H)+ (ES+), at 5.26 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.31 (s, 6H), 5.57 (s, 2H), 7.00 (s, 2H),7.11-7.25 (m, 3H), 7.51 (dd, J=7.8, 5.0, 1H), 8.47 (dd, J=7.9, 1.6, 1H),8.83 (dd, J=4.9, 1.6, 1H)

2-[6-Methoxy-5-(methylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (172)

The title compound (266 mg, 0.55 mmol) was prepared in three steps fromtert-butyl(6-{[(2-chloropyridin-3-yl)sulfonyl]amino}-2-methoxypyridin-3-yl)methylcarbamate(IntC8) (755 mg, 1.76 mmol), 2,4,6-trifluorobenzylamine (1.13 g, 7.01mmol) and N,N-diisopropylethylamine (0.46 mL, 2.64 mmol) in MeCN (10 mL)at 120° C. for 12 hours; followed by 1,1′-carbonyldiimidazole (832 mg,5.13 mmol) and triethylamine (358 uL, 2.57 mmol) using the methods of(95); followed by TFA (2 mL) in DCM (3 mL) at rt using the method of(179), step 2.

LCMS (Method B): m/z 480.1 (M+H)+ (ES+), at 4.62 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.70 (d, J=5.0, 3H), 3.78 (s, 3H), 5.53 (s,2H), 5.77 (d, J=5.0, 1H), 6.73 (d, J=8.2, 1H), 6.87 (d, J=7.8, 1H), 7.14(t, J=8.9, 2H), 7.46 (dd, J=7.8, 5.0, 1H), 8.17-8.42 (m, 1H), 8.60-8.79(m, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (175)

The title compound (110 mg, 0.23 mmol) was prepared in two steps from2-chloro-N-(6-methoxy-5-methylpyridin-2-yl)pyridine-3-sulfonamide(IntC11) (320 mg, 1.02 mmol) and 2,6-difluoro-4-methoxybenzylamine (212mg, 1.22 mmol); followed by 1,1′-carbonyldiimidazole (403 mg, 2.49 mmol)and triethylamine (173 uL, 1.24 mmol) using the methods of (95).

LCMS (Method B): m/z 477.1 (M+H)+ (ES+), at 4.96 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.16 (s, 3H), 3.71 (s, 3H), 3.80 (s, 3H),5.50 (s, 2H), 6.65 (s, 1H), 6.68 (s, 1H), 6.98 (d, J=7.3, 1H), 7.47 (dd,J=7.8, 5.0, 1H), 7.69 (dd, J=7.3, 0.9, 1H), 8.41 (dd, J=7.8, 1.4, 1H),8.79 (dd, J=4.8, 1.6, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-[5-methyl-6-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (184)

The title compound (150 mg, 0.32 mmol) was prepared in three steps fromtert-butyl(5-{[(2-chloropyridin-3-yl)sulfonyl]amino}-3-methylpyridin-2-yl)methylcarbamate(IntC13) (660 mg, 1.60 mmol), 2,6-difluoro-4-methoxybenzylamine (1.11 g,6.41 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.20 mmol) in MeCN(10 mL) at 120° C. for 12 hours; followed by 1,1′-carbonyldiimidazole(688 mg, 1.20 mmol) and triethylamine (296 uL, 2.12 mmol) using themethods of (95); followed by TFA (2 mL) in DCM (3 mL) at rt using themethod of (179), step 2.

LCMS (Method B): m/z 476.1 (M+H)+ (ES+), at 4.23 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 1.84 (s, 3H), 2.65 (d, J=4.5, 3H), 3.52 (s,3H), 5.30 (s, 2H), 6.23 (d, J=4.5, 1H), 6.46 (s, 1H), 6.49 (s, 1H), 6.97(dd, J=2.5, 1.0, 1H), 7.26 (dd, J=7.9, 4.9, 1H), 7.60 (d, J=2.3, 1H),8.24 (dd, J=7.9, 1.6, 1H), 8.59 (dd, J=4.9, 1.6, 1H)

2-(1,3-Benzothiazol-6-yl)-4-(2,6-difluoro-4-methoxybenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (182)

The title compound (60 mg, 0.12 mmol) was prepared in two steps fromN-(1,3-benzothiazol-6-yl)-2-chloropyridine-3-sulfonamide (IntC9) (300mg, 0.92 mmol) and 2,6-difluoro-4-methoxybenzylamine (176 mg, 1.01 mmol)at 140° C. in a sealed tube; followed by triphosgene (288 mg, 0.97 mmol)in 1,4-dioxane (5 mL) at 110° C. for 16 h using the methods of (95) then(63).

LCMS (Method B): m/z 510.0 (M+H)+ (ES+), at 4.39 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.76 (s, 3H), 5.56 (s, 2H), 6.72 (d, J=9.8,2H), 7.51-7.58 (m, 2H), 8.23 (d, J=8.6, 1H), 8.34 (s, 1H), 8.51 (d,J=7.0, 1H), 8.86 (d, J=5.5, 1H), 9.56 (s, 1H)

2-(5-Methoxy-6-methylpyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (176)

The title compound (52 mg, 0.11 mmol) was prepared in two steps from(IntC14) (88 mg, 0.28 mmol), 2,4,6-trifluorobenzyl amine (58 mg, 0.36mmol) and N,N-diisopropylethylamine (100 uL, 0.57 mmol); followed by1,1′-carbonyldiimidazole (110 mg, 0.68 mmol) and triethylamine (45 uL,0.32 mmol) using the methods of (97).

LCMS (Method B): m/z 465.1 (M+H)+ (ES+), at 4.32 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.44 (s, 3H), 3.82 (s, 3H), 5.60 (s, 2H),7.19-7.23 (m, 2H), 7.45 (d, J=1.8, 1H), 7.55 (dd, J=8.0, 4.8, 1H), 8.06(d, J=1.8, 1H), 8.53 (dd, J=7.8, 1.4, 1H), 8.87 (dd, J=5.0, 1.8, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (186)

The title compound (155 mg, 0.32 mmol) was prepared in three steps fromtert-butyl(5-{[(2-chloropyridin-3-yl)sulfonyl]amino}-2-methoxypyridin-3-yl)methylcarbamate(IntC15) (214 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (0.28 mL,2.0 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) in MeCN (3mL) at 120° C. for 6 hours; followed by 1,1′-carbonyldiimidazole (350mg, 2.16 mmol) and triethylamine (0.15 mL, 1.08 mmol) using the methodsof (95); followed by TFA (2 mL) in DCM (3 mL) at rt using the method of(179), step 2.

LCMS (Method B): m/z 492.0 (M+H)+ (ES+), at 4.53 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.61 (d, J=5.0, 3H), 3.71 (s, 3H), 3.89 (s,3H), 5.50 (s, 2H), 5.70 (d, J=5.0, 1H), 6.57 (d, J=1.8, 1H), 6.67 (d,J=10.1, 2H), 7.29 (d, J=2.3, 1H), 7.45 (dd, J=7.8, 4.6, 1H), 8.42 (dd,J=8.0, 1.6, 1H), 8.78 (dd, J=4.8, 1.6, 1H)

2-[5-Methoxy-6-(methylamino)pyridin-3-yl]-4-(2,6-difluoro-4-methoxybenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (177)

The title compound (133 mg, 0.27 mmol) was prepared in three steps fromtert-butyl(5-{[(2-chloropyridin-3-yl)sulfonyl]amino}-3-methoxypyridin-2-yl)methylcarbamate (IntC17) (214 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine(0.28 mL, 2.0 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) inMeCN (3 mL) at 120° C. for 6 hours; followed by 1,1′-carbonyldiimidazole(259 mg, 1.6 mmol) and triethylamine (0.11 mL, 0.8 mmol) using themethods of (95); followed by TFA (2 mL) in DCM (3 mL) at rt using themethod of (179), step 2.

LCMS (Method B): m/z 492.1 (M+H)+ (ES+), at 4.17 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.81 (d, J=4.6, 3H), 3.71 (s, 3H), 3.72 (s,3H), 5.50 (s, 2H), 6.58 (d, J=4.6, 1H), 6.67 (d, J=10.1, 2H), 6.88 (d,J=1.4, 1H), 7.45 (dd, J=7.6, 4.8, 1H), 7.54 (d, J=1.4, 1H), 8.43 (d,J=6.9, 1H), 8.78 (d, J=3.7, 1H)

Route 54-(2-Chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (91) Step 1: Preparation of4-[(2-chloro-6-fluorobenzyl)amino]-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide

A solution of 4-Chloro-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide(IntD1) (0.5 g, 1.50 mmol), 2-chloro-6-fluoro-benzylamine (0.26 g, 1.67mmol) and K₂CO₃ (0.41 g, 3.0 mmol) in DMF (10 mL) was heated at 130° C.for 4 h. The mixture was added to saturated aqueous NaHCO₃ (50 mL),extracted with EtOAc (3×25 mL) and the combined organic phases driedover Na₂SO₄ and concentrated in vacuo. Purification by gradient columnchromatography eluting with 0-45% EtOAc in hexane yielded the titlecompound (40 mg, 0.09 mmol).

LCMS (Method B): (ESI+ve) 451.8. [M+H]⁺.

Step 2: Preparation of4-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide

A solution of4-[(2-chloro-6-fluorobenzyl)amino]-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide(0.04 g, 0.09 mmol) and 1,1′-carbonyldiimidazole (56 mg, 0.34 mmol) in1,2-dichloroethane (10 mL) was heated for 30 min at 100° C., then cooledand concentrated in vacuo. Purification by gradient columnchromatography eluting with 0-30% EtOAc in hexane yielded the titlecompound (10 mg, 0.02 mmol).

LCMS (Method B): m/z 478.2, 480.1 (M+H)+ (ES+), at 3.93 min, 100% ¹HNMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.82 (s, 3H), 5.49 (s, 2H),6.85-6.99 (m, 2H), 7.08 (d, J=8.5, 1H), 7.19-7.30 (m, 1H), 7.33-7.47 (m,2H), 7.72 (d, J=5.8, 1H), 8.91 (d, J=6.1, 1H), 9.07 (s, 1H)4-(4-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (92)

The title compound (110 mg, 0.23 mmol) was prepared in two steps from4-Chloro-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide (IntD1) (300 mg,0.90 mmol), 2-fluoro-4-chlorobenzylamine (146 mg, 0.90 mmol) and K₂CO₃(378 mg, 2.73 mmol); followed by 1,1′-carbonyldiimidazole (0.22 g, 1.32mmol) using the methods of (91).

LCMS (Method B): m/z 478.2, 480.0 (M+H)+ (ES+), at 4.28 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.73 (s, 3H), 3.82 (s, 3H), 5.40 (br s, 2H),6.98-7.14 (m, 3H), 7.22-7.30 (m, 1H), 7.31-7.40 (m, 1H), 7.48-7.64 (m,2H), 8.84 (d, J=6.1, 1H), 9.11 (s, 1H)

Route 64-(2-Chloro-6-fluorobenzyl)-2-(pyridin-2-ylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (128)

A mixture of (IntE1) (0.3 g, 0.88 mmol), 2-(bromomethyl)pyridine (0.33g, 1.32 mmol) and Cs₂CO₃ (0.86 g, 2.64 mmol) in 1,4-dioxane (15 mL) washeated at 75° C. for 8 h. After cooling to rt, H₂O was added and themixture extracted with EtOAc, dried over Na₂SO and concentrated invacuo. Purification by gradient column chromatography eluting with 0-30%EtOAc in hexane yielded the title compound (150 mg, 0.35 mmol).

LCMS (Method B): m/z 432.1, 434.1 (M+H)+ (ES+), at 4.20 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 5.27 (s, 2H), 5.54 (s, 2H), 6.92-7.05 (m,1H), 7.13-7.50 (m, 6H), 7.65 (dt, J=16.3, 8.0, 2H), 7.90 (d, J=7.6, 1H),8.55 (d, J=4.3, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-(cyclohexylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (64)

The title compound (25 mg, 0.06 mmol) was prepared from (IntE1) (0.3 g,0.88 mmol), 2-(bromomethyl)cyclohexane (0.18 g, 1.05 mmol) and K₂CO₃(0.36 g, 2.60 mmol) using the methods of (128).

LCMS (Method B): m/z 437.2, 439.2 (M+H)+ (ES+), at 5.40 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 0.79-0.99 (m, 2H), 1.01-1.31 (m, 3H),1.48-1.73 (m, 6H), 4.14 (d, J=6.1, 2H), 5.53 (s, 2H), 7.18-7.30 (m, 1H),7.35-7.51 (m, 3H), 7.58-7.68 (m, 1H), 7.68-7.79 (m, 1H), 7.86 (d, J=7.9,1H)

4-(2-Chloro-6-fluorobenzyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (117)

The title compound (150 mg, 0.34 mmol) was prepared from (IntE1) (0.3 g,0.88 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (0.20 g, 1.05 mmol) andK₂CO₃ (0.36 g, 2.60 mmol) using the methods of (128).

LCMS (Method B): m/z 439.2, 441.2 (M+H)+ (ES+), at 4.42 min, >95%

¹H NMR: (400 MHz, DMSO+D₂O) δ: 0.95-1.25 (m, 3H), 1.43 (d, J=12.2, 2H),3.16 (t, J=10.8, 2H), 3.58-3.85 (m, 4H), 5.40 (br s, 2H), 7.14 (d,J=9.2, 1H), 7.22-7.47 (m, 3H), 7.59 (d, J=8.2, 1H), 7.74 (t, J=7.8, 1H),7.85 (d, J=7.6, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-[(3-methyloxetan-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (118)

The title compound (123 mg, 0.29 mmol) was prepared from (IntE1) (0.3 g,0.88 mmol), 3-(bromomethyl)-3-methyloxetane (0.21 g, 1.32 mmol) andCs₂CO₃ (0.86 g, 2.64 mmol) using the methods of (128).

LCMS (Method B): m/z 425.2, 427.2 (M+H)+ (ES+), at 4.22 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 1.21 (d, J=1.8, 3H), 3.92-4.15 (m, 4H), 4.48(dd, J=5.6, 2.3, 2H), 5.47 (br s, 2H), 7.13-7.29 (m, 1H), 7.29-7.51 (m,3H), 7.59-7.72 (m, 1H), 7.81 (t, J=7.5, 1H), 7.93 (d, J=7.6, 1H)

4-(2-Chloro-6-fluorobenzyl)-2-[(5-methyl-1,2-oxazol-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (129)

The title compound (0.16 g, 0.37 mmol) was prepared from (IntE1) (0.3 g,0.88 mmol), 3-(bromomethyl)-5-methyl-1,2-oxazole (0.11 g, 0.63 mmol) andCs₂CO₃ (0.86 g, 2.64 mmol) using the methods of (128).

LCMS (Method B): m/z 436.2, 438.2 (M+H)+ (ES+), at 4.47 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.36 (s, 3H), 5.00 (s, 2H), 5.48 (s, 2H),6.09 (s, 1H), 7.15-7.47 (m, 4H), 7.67 (d, J=8.5, 1H), 7.76-7.87 (m, 1H),7.93 (d, J=7.9, 1H)

4-(4-Chloro-2-fluorobenzyl)-2-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (134)

The title compound (0.17 g, 0.38 mmol) was prepared from (IntE2) (0.6 g,1.76 mmol), 5-(Bromomethyl)-1,3-dimethyl-1H-pyrazole (IntE5) (0.40 g,1.2 mmol) and K₂CO₃ (1.21 g, 8.8 mmol) using the methods of (128).

LCMS (Method B): m/z 449.1, 451.2 (M+H)+ (ES+), at 4.21 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 2.03 (s, 3H), 3.73 (s, 3H), 4.99 (s, 2H),5.47 (s, 2H), 5.87 (s, 1H), 7.16-7.26 (m, 1H), 7.30-7.47 (m, 3H), 7.64(d, J=8.2, 1H), 7.75-7.85 (m, 1H), 7.93 (d, J=7.6, 1H)

4-{[4-(2,6-Difluorobenzyl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl]methyl}-2-fluorobenzonitrile(65)

A mixture of (IntE3) (100 mg, 0.31 mmol),4-(bromomethyl)-2-fluorobenzonitrile (165 mg, 0.77 mmol) and K₂CO₃ (107mg, 0.77 mmol) in DMF (5 mL) was heated in a CEM Discover microwavereactor at 100° C. for 3 h before EtOAc (40 mL) and H₂O (10 mL) wereadded and the phases were separated. The organic phase was washed withbrine (5×10 mL), dried over MgSO₄ and concentrated in vacuo.Purification by preparative HPLC (method A) yielded the title compound(11 mg, 0.02 mmol).

LCMS (Method B): m/z 458.3 (M+H)+ (ES+), at 4.87 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 5.13 (s, 2H), 5.48 (s, 2H), 7.06-7.12 (m,2H), 7.33-7.46 (m, 4H), 7.63-7.70 (m, 1H), 7.85 (t, J=7.3, 1H), 7.94 (t,J=6.4, 2H)

4-(2,6-Difluorobenzyl)-2-[2-(3-methoxyphenyl)ethyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (66)

A mixture of (IntE3) (50 mg, 0.15 mmol),1-(2-bromoethyl)-3-methoxybenzene (37 μl, 0.23 mmol) and K₂CO₃ (32.0 mg,0.23 mmol) in DMF (3 mL) in a sealed tube was heated at 100° C.overnight. After cooling to rt, further1-(2-bromoethyl)-3-methoxybenzene (25 μl, 0.15 mmol) and K₂CO₃ (21.3 mg,0.15 mmol) were added and the mixture was heated in a CEM Discovermicrowave reactor at 100° C. for 1 h. EtOAc (40 mL) and H₂O (10 mL) wereadded and the phases were separated. The organic phase was washed withwater (4×10 mL) and brine (10 mL), dried over MgSO₄ and concentrated invacuo. Purification by preparative HPLC (method A) yielded the titlecompound (26.4 mg, 0.06 mmol).

LCMS (Method B): m/z 459.3 (M+H)+ (ES+), at 5.12 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.88 (t, J=7.5, 2H), 3.66 (s, 3H), 4.02 (t,J=7.5, 2H), 5.45 (s, 2H), 6.67-6.76 (m, 3H), 7.04-7.15 (m, 3H),7.34-7.44 (m, 2H), 7.63 (d, J=8.5, 1H), 7.76-7.84 (m, 2H)

4-(2,6-Difluorobenzyl)-2-[(2-oxo-1,2-dihydroquinolin-4-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (126)

A mixture of (IntE3) (50 mg, 0.15 mmol),4-(bromomethyl)quinolin-2(1H)-one (184 mg, 0.77 mmol) and K₂CO₃ (107 mg,0.77 mmol) in DMF (5 mL) in a sealed tube was heated at 100° C. forapproximately 4 h. 4-(Bromomethyl)quinolin-2(1H)-one (37 mg, 0.15 mmol)was added and the mixture heated at 100° C. overnight, before theaddition of further 4-(bromomethyl)quinolin-2(1H)-one (37 mg, 0.15 mmol)and K₂CO₃ (21.3 mg, 0.15 mmol) and heating in a CEM Discover microwavereactor at 100° C. for 1 h. EtOAc (40 mL) and brine (10 mL) were added,the phases were separated and the organic phase was washed with brine(4×10 mL), dried over MgSO₄ and concentrated in vacuo. Purification bypreparative HPLC (method A) yielded the title compound (5.8 mg, 0.01mmol).

LCMS (Method B): m/z 482.2 (M+H)+ (ES+), at 3.88 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 5.31 (s, 2H), 5.52 (s, 2H), 6.13 (s, 1H),7.06-7.14 (m, 2H), 7.23 (t, J=8.0, 1H), 7.35 (d, J=8.0, 1H), 7.41 (t,J=8.3, 1H), 7.48 (t, J=7.5, 1H), 7.53 (t, J=7.3, 1H), 7.74 (d, J=8.5,1H), 7.89 (t, J=8.5, 2H), 7.98 (d, J=7.8, 1H), 11.78 (s, 1H)

4-(2,6-Difluorobenzyl)-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (119)

A mixture of (IntE3) (50 mg, 0.15 mmol),4-(chloromethyl)-2-methylthiazole hydrochloride (71.0 mg, 0.39 mmol), KI(5.1 mg, 0.03 mmol) and K₂CO₃ (74.6 mg, 0.54 mmol) in DMF (3 mL) washeated in a CEM Discover microwave reactor at 100° C. for 3 h. Further4-(chloromethyl)-2-methylthiazole hydrochloride (28.4 mg, 0.15 mmol), KI(5.1 mg, 0.03 mmol) and K₂CO₃ (42.6 mg, 0.31 mmol) were added and themixture heated in a CEM Discover microwave reactor at 100° C. for 3 h.EtOAc (40 mL) and brine (10 mL) were added, the phases were separatedand the organic phase was washed with brine (3×10 mL), dried over Na₂SO₄and concentrated in vacuo. Purification by preparative HPLC (method A)yielded the title compound (9.1 mg, 0.02 mmol).

LCMS (Method B): m/z 436.2 (M+H)+ (ES+), at 4.18 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.58 (s, 3H), 5.04 (s, 2H), 5.47 (s, 2H),7.01-7.08 (m, 2H), 7.14 (s, 1H), 7.35-7.43 (m, 2H), 7.65 (d, J=8.5, 1H),7.80 (t, J=7.8, 1H), 7.88 (d, J=7.8, 1H)

4-(2,6-Difluorobenzyl)-2-[(3,4-dimethoxypyridin-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (121)

A mixture of (IntE3) (100 mg, 0.31 mmol),2-(chloromethyl)-3,4-dimethoxypyridine hydrochloride (173 mg, 0.77mmol), KI (10.2 mg, 0.06 mmol) and K₂CO₃ (170 mg, 1.23 mmol) in DMF (6mL) was heated at 100° C. for 1 d. After cooling to rt, EtOAc (40 mL)and H₂O (10 mL) were added, the phases were separated and the organicphase was washed with H₂O (4×10 mL), dried over MgSO₄ and concentratedin vacuo. Purification by preparative HPLC (method A) yielded the titlecompound (20 mg, 0.04 mmol).

LCMS (Method B): m/z 476.1 (M+H)+ (ES+), at 4.19 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 3.79 (s, 3H), 3.87 (s, 3H), 5.12 (s, 2H),5.45 (s, 2H), 6.95 (d, J=5.5, 1H), 7.04 (t, J=8.3, 2H), 7.34-7.41 (m,2H), 7.69 (d, J=8.3, 1H), 7.79 (t, J=8.3, 2H), 7.88 (d, J=5.5, 1H)

4-(2,6-Difluorobenzyl)-2-[(1-methyl-1H-imidazol-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (131)

Diisopropyl azodicarboxylate (0.16 ml, 0.77 mmol) was added dropwise toa solution of (IntE3) (100 mg, 0.31 mmol),(1-methyl-1H-imidazol-2-yl)methanol (86 mg, 0.77 mmol) andtriphenylphosphine (202 mg, 0.77 mmol) in THF (2 mL) at 0° C. Thereaction mixture was allowed to warm to rt with stirring overnightbefore concentration in vacuo. Purification by preparative HPLC (methodA) yielded the title compound (28 mg, 0.07 mmol).

LCMS (Method B): m/z 419.2 (M+H)+ (ES+), at 3.38 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.65 (s, 3H), 5.04 (s, 2H), 5.46 (s, 2H),6.67 (s, 1H), 7.02 (s, 1H), 7.04-7.10 (m, 2H), 7.35-7.43 (m, 2H), 7.70(d, J=8.5, 1H), 7.82 (t, J=7.5, 1H), 7.88 (d, J=7.8, 1H)

4-(2,4,6-Trifluorobenzyl)-2-[(2-oxo-1,2-dihydroquinolin-4-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (156)

A mixture of (IntE4) (60 mg, 0.18 mmol),4-(bromomethyl)quinolin-2(1H)-one (104 mg, 0.44 mmol) and K₂CO₃ (60.6mg, 0.44 mmol) in DMF (5 mL) was heated in a sealed tube at 100° C. for1 h. After concentration in vacuo, purification by gradient columnchromatography, eluting with 0-100% EtOAc in iso-hexane, followed bypreparative HPLC (method B) yielded the title compound (10 mg, 0.02mmol).

LCMS (Method B): m/z 500.1 (M+H)+ (ES+), at 4.03 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 5.30 (s, 2H), 5.47 (s, 2H), 6.11 (s, 1H),7.12-7.27 (m, 3H), 7.35 (d, J=8.0, 1H), 7.44-7.60 (m, 2H), 7.75 (d,J=8.5, 1H), 7.85-7.94 (m, 2H), 7.96-8.04 (m, 1H), 11.78 (s, 1H)

4-(2,6-Difluorobenzyl)-2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (120)

A mixture of (IntE3) (100 mg, 0.31 mmol),4-(2-chloroethyl)-3,5-dimethylisoxazole (123 mg, 0.77 mmol), KI (10.2mg, 0.06 mmol) and K₂CO₃ (107 mg, 0.77 mmol) in DMF (5 mL) was heated ina CEM Discover microwave reactor for 3 h. EtOAc (40 mL) and H₂O (10 mL)were added, the phases were separated and the organic phase was washedwith H₂O (4×10 mL) and brine (20 mL), dried over MgSO₄ and concentratedin vacuo. Purification by preparative HPLC (method A) yielded the titlecompound (24 mg, 0.05 mmol).

LCMS (Method B): m/z 448.2 (M+H)+ (ES+), at 4.33 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 2.03 (s, 3H), 2.09 (s, 3H), 2.65 (t, J=6.8,2H), 3.90 (t, J=6.8, 2H), 5.45 (s, 2H), 7.05 (m, 2H), 7.35-7.43 (m, 2H),7.68 (d, J=8.5, 1H), 7.78-7.84 (m, 2H)

4-(2,6-Difluorobenzyl)-2-[(1-methyl-1H-indazol-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (125)

The title compound (11 mg, 0.02 mmol) was prepared from (IntE3) (50 mg,0.154 mmol), 3-(chloromethyl)-1-methyl-1H-indazole (69.6 mg, 0.39 mmol),KI (5.1 mg, 0.03 mmol) and K₂CO₃ (53.3 mg, 0.39 mmol) in DMF (3 mL) in aCEM Discover microwave reactor (100° C., 1 h) using the methods of(120).

LCMS (Method B): m/z 469.2 (M+H)+ (ES+), at 4.66 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.95 (s, 3H), 5.32 (s, 2H), 5.47 (s, 2H),7.03-7.10 (m, 3H), 7.34-7.43 (m, 3H), 7.57 (d, J=8.5, 1H), 7.66 (d,J=8.5, 1H), 7.71 (d, J=8.0, 1H), 7.80 (t, J=7.3, 1H), 7.92 (d, J=7.8,1H)

4-(2,6-Difluorobenzyl)-2-(1-ethylpiperidin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide (133)

The title compound (42 mg, 0.09 mmol) was prepared from (IntE3) (100 mg,0.31 mmol), 3-chloro-1-ethylpiperidine hydrochloride (142 mg, 0.77mmol), KI (10.2 mg, 0.06 mmol) and K₂CO₃ (107 mg, 0.77 mmol) in DMF (5mL) in a CEM Discover microwave reactor (100° C., 1 h) using the methodsof (120).

LCMS (Method B): m/z 436.2 (M+H)+ (ES+), at 4.46 and 4.63 min, >95%

¹H NMR: (400 MHz, DMSO) δ: 0.92-1.00 (m, 3H), 1.53-1.66 (m, 2H),2.09-2.55 (m, 4H), 2.65-3.00 (m, 3H), 3.68-3.75 (m, 2H), 5.39-5.51 (m,2H), 7.04-7.10 (m, 2H), 7.35-7.43 (m, 2H), 7.63-7.66 (m, 1H), 7.77-7.82(m, 1H), 7.86-7.91 (m, 1H)

Route 74-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (173)

The title compound (182 mg, 0.40 mmol) was prepared from2-(5,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF1) (181 mg, 0.60 mmol), 2,6-difluoro-4-methoxybenzylbromide (169 mg, 0.71 mmol) and K₂CO₃ (123 mg, 0.89 mmol) in DMF (3 mL)using the methods of (115).

LCMS (Method B): m/z 461.1 (M+H)+ (ES+), at 4.53 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.27 (s, 3H), 2.39 (s, 3H), 3.71 (s, 3H),5.49 (s, 2H), 6.65 (s, 1H) 6.67 (s, 1H), 7.20 (d, J=7.8, 1H), 7.46 (dd,J=8.0, 4.8, 1H), 7.69 (d, J=7.8, 1H), 8.39 (dd, J=8.0, 1.6, 1H), 8.79(dd, J=5.0, 1.8, 1H)

4-(2,6-Difluoro-4-methoxybenzyl)-2-(4,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (174)

The title compound (85 mg, 0.18 mmol) was prepared from2-(4,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF2) (110 mg, 0.36 mmol), 2,6-difluoro-4-methoxybenzylbromide (103 mg, 0.43 mmol) and K₂CO₃ (75 mg, 0.54 mmol) in DMF (3 mL)using the methods of (115).

LCMS (Method B): m/z 461.1 (M+H)+ (ES+), at 4.53 min, 95%

¹H NMR: (400 MHz, DMSO) δ: 2.29 (s, 3H), 2.40 (s, 3H), 3.71 (s, 3H),5.49 (s, 2H), 6.65 (s, 1H), 6.67 (s, 1H), 7.13 (s, 1H), 7.22 (s, 1H),7.47 (dd, J=7.8, 5.0, 1H), 8.39 (dd, J=8.0, 1.6, 1H), 8.80 (dd, J=4.81,1.60, 1H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (180)

The title compound (74 mg, 0.15 mmol) was prepared from2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF3) (101 mg, 0.30 mmol), 2-chloro-4,6-difluorobenzylalcohol (IntA22) (59 mg, 0.33 mmol), TMAD (57 mg, 0.33 mmol) andtriphenyl phosphine (86 mg, 0.33 mmol) in DCM (3 mL) using the methodsof (162).

LCMS (Method B): m/z 497.0, 499.0 (M+H)+ (ES+), at 5.26 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.86 (s, 6H), 5.53 (s, 2H), 6.40 (s, 2H),7.24-7.31 (m, 1H), 7.34 (d, J=8.7, 1H), 7.47 (dd, J=7.8, 5.0, 1H), 8.44(dd, J=7.8, 1.4, 1H), 8.79 (dd, J=4.8, 1.6, 1H)

4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (185)

The title compound (118 mg, 0.24 mmol) was prepared from2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one1,1-dioxide (IntF4) (101 mg, 0.30 mmol), 2-chloro-4,6-difluorobenzylalcohol (IntA22) (59 mg, 0.33 mmol), TMAD (103 mg, 0.6 mmol) andtriphenyl phosphine (157 mg, 0.6 mmol) in DCM (3 mL) using the methodsof (162).

LCMS (Method B): m/z 497.0, 499.0 (M+H)+ (ES+), at 4.69 min, 100%

¹H NMR: (400 MHz, DMSO) δ: 3.72 (s, 3H), 3.88 (s, 3H), 5.55 (s, 2H),7.25-7.38 (m, 3H), 7.48 (dd, J=7.8, 5.0, 1H), 7.70 (d, J=2.3, 1H), 8.46(dd, J=7.8, 1.4, 1H), 8.79 (dd, J=5.0, 1.4, 1H).

Biological Testing Membrane Preparation

cDNA encoding the human Orexin-2 receptor was transfected into HEK293cells using the transfection reagent Genejuice (Novagen). Fourty-eighthours after transfection, cells were harvested and washed twice with icecold phosphate-buffered saline. The pellet was resuspended in ice-coldbuffer containing 20 mM Tris-HCl, pH 7.4, 1 mM EDTA and homogenised withan Ultraturax for 30 s at maximum speed. After centrifugation at 48,000g for 30 min at 4° C., the pellet was resuspended and spun again. Thefinal pellet was resuspended and frozen at −80° C. before use. Proteinconcentration was determined using the BCA protein assay method.

³H-EMPA Radioligand Binding Assay

After thawing, membrane homogenates were re-suspended in the bindingbuffer (8.5 mM HEPES, pH 7.4, 1.3 mM CaCl₂, 1.2 mM MgSO₄, 118 mM NaCl,4.7 mM KCl, 4 mM NaHCO₃, 1.2 mM KH₂PO₄, 11 mM Glucose) to a final assayconcentration of 2.5 protein per well. Saturation isotherms weredetermined by the addition of various concentrations of ³H-EMPA(Malherbe et al, Br. J. Pharmacol. 2009, 156, 1326) in a total reactionvolume of 250 μL for 60 min at room temperature. At the end of theincubation, membranes were filtered onto a unifilter, a 96-well whitemicroplate with bonded GF/B filter pre-incubated with 0.5%polyethylenimine, with a Tomtec cell harvester and washed 4 times withdistilled water. Non-specific binding (NSB) was measured in the presenceof 10 μM(2S)-1-(3,4-Dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanonehydrochloride (TCS OX2 29, Tocris bioscience, catalogue number 3371).Radioactivity on the filter was counted (1 min) on a microbeta counterafter addition of 50 μL of scintillation fluid. For inhibitionexperiments, membranes were incubated with ³H-EMPA at a concentrationequal to the K_(D) value of the radioligand and 10 concentrations of theinhibitory compound (0.001-10 μM). IC₅₀ values were derived from theinhibition curve and the equilibrium dissociation constant (K₁) valueswere calculated using the Cheng-Prussoff equation. Data is given inTable 1 for all examples.

Ex vivo orexin-2 receptor occupancy Male Sprague Dawley rats were dosedorally with either vehicle, example 145, (0.3-10 mg/kg po) or example100, (1 mg/kg, po). Vehicle for example 145 was 90% PEG400/10% Tween-80;for example 100 10% DMAC+10% Solutol+80% (10% HPβCD in water). 1 hpost-dose, animals were sacrificed and brains removed. A coronal blockcontaining the cortex was rapidly frozen in isopentane for sectioningand autoradiography. 20 μm thick sections were mounted onto slides andincubated with [³H]EMPA (total binding) or [³H]EMPA and 1 μM TCS OX2 29(non-specific binding) for 20 min at rt. Binding was terminated byaspiration and washing with ice-cold assay buffer and allowed to airdry. Levels of bound radioactivity in the sections were determined usinga beta imager over a 16 h period. Occupancy was determined as meanspecific binding with the vehicle treated control taken as 100%. Example145 occupied cortical orexin-2 receptors in a dose dependent manner,with an estimated ED50 of 5.8 mg/kg (po). At a dose of 1 mg/kg, example100 occupied 57% of orexin-2 receptors, suggesting that the ED50 valueis <1 mg/kg (po).

Rat Telemetered Sleep Study

Example 100 was assessed for activity in a rat CT18 sleep model. Adultmale CD rats (250-300 g) were implanted with telemetric probes fixed tothe skull to record cortical electroencephalogram (EEG), and withtelemetric probes fixed to the skeletal muscles of the neck to recordelectromyogram (neck EMG), and allowed to recover for 3 weeks tore-establish normal sleep patterns. Rats were administered with example100 (3, 10 and 30 mg/kg, po) or vehicle (80% v/v PEG400, 20% v/vCremophor EL, 2 ml/kg) at Circadian Time (CT) 18, six hours after lightsoff. EEG and neck EMG traces were recorded for 5 hours after treatmentand analysed to determine time spent awake and in NREM sleep and REMsleep. ANOVA (analysis of variance) statistical analysis over 3 hourspost-treatment indicated that at a dose of e.g. 3 mg/kg example 100induced a statistically significant decrease in time spent awake, withstatistically significant increases in REM and NREM sleep. The positivecontrol zolpidem confirmed experiment validity, demonstrating a hypnoticeffect which was characterized by a decrease in NREM latency, a decreasein time spent awake and an increase in NREM sleep.

The invention claimed is:
 1. A method of treatment of a disorder,wherein the disorder is insomnia, a headache disorder, obesity, amovement disorder, an anxiety disorder, a panic disorder, a binge eatingdisorder, a compulsive disorder, an impulse control disorder andAlzheimer's disease, comprising administering an effective amount of thecompound of formula (1) to a subject in need thereof, wherein thecompound of formula (1) is

wherein Y₂, Y₃ are independently a carbon or a nitrogen atom; and Y₄ isC-alkyl, C-halogen, C—H or N; and W is a methylene group substituted bysubstituted aryl, or optionally substituted heteroaryl orheterocycloalkyl moiety, wherein the substituents and optionalsubstituents forming part of W are selected from the group consisting ofhalo, alkyl, hydroxyl and alkoxy; and X comprises an optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted heterocycloalkylmoiety, wherein X is not cyclopropyl and wherein the optionalsubstituents forming part of X are selected from the group consisting offluoro, chloro, bromo, iodo, oxo, C₁₋₄ alkyl, C₁₋₄ alkylsulfanyl, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulphonyl, C₃₋₆ cycloalkyl, hydroxy, C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄ alkylamino, C₂₋₄ alkenylamino, di-C₁₋₄alkylamino, C₁₋₄ acylamino, phenyl, phenylamino, benzoylamino,benzylamino, phenylamido, carboxy, C₁₋₄ alkoxycarbonyl, phenyl-C₁₋₁₀alkoxycarbonyl, carbamoyl, mono-C₁₋₄ carbamoyl, di-C₁₋₄ carbamoyl andany of the above in which a hydrocarbyl moiety is itself substituted byhalo, cyano, hydroxy, C₁₋₂ alkoxy, amino, nitro, carbamoyl, carboxy orC₁₋₂ alkoxycarbonyl.
 2. The method of claim 1 wherein Y₁ is nitrogen. 3.The method of claim 1 wherein Y₄ is CH or N.
 4. The method of claim 1,wherein X is an optionally substituted heteroaryl or heterocycloalkylmoiety.
 5. The method of claim 4, wherein X is selected from


6. The method of claim 1, wherein the disorder is migraine, clusterheadache or other headache disorders.
 7. The method of claim 1, whereinthe disorder is obesity.
 8. The method of claim 1, wherein the disorderis movement disorders, anxiety disorders, panic disorders, binge eatingdisorder, compulsive disorders, impulse control disorders, orAlzheimer's disease.
 9. The method of claim 6, wherein the headachedisorder is migraine or cluster headache.
 10. The method of claim 1wherein the compound is selected from the group consisting of4-(1,3-benzodioxol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,4-dimethoxyphenyl)-4-(3-fluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,5-dimethoxyphenyl)-4-(3-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,3-{[2-(3,4-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl]methyl}benzonitrile,4-benzyl-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,5-dimethoxyphenyl)-4-(3-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,4-dimethoxyphenyl)-4-(4-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,4-dimethoxyphenyl)-4-(4-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(3-bromobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,4-(3-fluoro-4-methoxybenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3-ethylphenyl)-4-(3-fluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(3-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,5-dimethoxyphenyl)-4-(2-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-fluorobenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,5-dimethoxyphenyl)-4-(2-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chlorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide, methyl3-{[2-(3,5-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl]methyl}-4-methoxybenzoate,2-(3,4-dimethoxyphenyl)-4-(2-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chlorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-4-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chlorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-fluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(4-chlorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-phenyl-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(4-ethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(4-acetylphenyl)-4-(2-chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(2,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(2-ethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(2-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(4-ethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(2,3-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(4-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-benzyl-4-(2-chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3-chlorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3-fluoro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(4-fluorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(2,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(2,5-difluorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(3-ethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-[4-(propan-2-yl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-4-fluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2,5-dimethylbenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide, methyl3-({2-[3-(methylsulfanyl)phenyl]-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl}methyl)-4-methoxybenzoate,4-(2-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-methylbenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chlorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-fluorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-fluorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-benzyl-4-(2-chlorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chlorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide, methyl3-{[2-(3,4-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl]methyl}-4-methoxybenzoate,4-(Cyclobutylmethyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(Cyclohexylmethyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,7-Fluoro-4-[1-(2-fluorophenyl)ethyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-Chloro-6-fluorobenzyl)-2-(cyclohexylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-{[4-(2,6-Difluorobenzyl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl]methyl}-2-fluorobenzonitrile,4-(2,6-Difluorobenzyl)-2-[2-(3-methoxyphenyl)ethyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,2-(3,4-Dimethoxyphenyl)-4-(2-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2,6-Dichlorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-Chloro-6-fluorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2,6-Dichlorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(3-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(4-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide, 4-(2-Chloro-6-fluorobenzyl)-2-{3-[(trifluoromethyl)sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,4-(2-Chloro-6-fluorobenzyl)-7-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide, 4-(2,6-Difluorobenzyl)-2-{3-[(trifluoromethyl)sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3 (4H)-one 1,1-dioxide,4-(2-Chloro-6-fluorobenzyl)-6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2,6-Dimethylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-Chloro-6-fluorobenzyl)-2-(3,4,5-trimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-Fluoro,6-methylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-Chloro-4-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide,4-(2-chloro-6-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide, and4-(2-Chloro-6-fluorobenzyl)-2-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one1,1-dioxide.